Compound

ABSTRACT

The present invention relates to certain spirooxindole derivatives of the formula I, and pharmaceutically acceptable salts thereof, which exhibit good analgesic properties and are particularly effective in the treatment of chronic pain.

TECHNICAL FIELD

[0001] The present invention relates to novel spirooxindole derivatives,and pharmaceutically acceptable salts thereof, with an analgesic effect.The compounds of the invention can thus be used in the prevention andtreatment of pain. In further aspects, the invention relates tocompounds for use in therapy; to processes for preparation of such newcompounds; to pharmaceutical compositions containing at least onecompound of the invention, or a pharmaceutically acceptable saltthereof, as active ingredient; and to the use of the active compounds inthe manufacture of medicaments for the medical use indicated above. Theinvention also relates to new intermediates for use in the preparationof the novel compounds.

BACKGROUND ART

[0002] Certain spirooxindole derivatives are known as intermediates inthe syntheses of vasopressin receptor ligands from U.S. Pat. No.5,728,723 (Elf Sanofi).

[0003] Patent applications WO 9741125 (SKB), WO 9711697 (MSD), WO9527712 (CEMAF), and WO 9315051 (Elf) also discloses spirooxindoles assynthetic intermediates.

[0004] Certain spirooxindole derivatives are known as local anestheticsfrom Kornet and Thio, Journal of Medicinal Chemistry 1976, 19, 892-8.This publication discloses racemic mixtures and biological studies werelimited to toxicity (LD₅₀) in mice and local anesthetic activity (ratsciatic nerve blocking) in which test the compounds were found inferiorto lidocaine. No analgesic effects of the spirooxindole derivatives arementioned.

[0005] However, there remains a need for new therapeutic agents to treatchronic pain. Chronic pain can be caused by injury to nerves or by avariety of lesions. As of today there is no clear understanding whysome, more or less visible injuries may elicit pain. Medical doctorsoften find even strong analgesics, such as opioids, distressfullyinefficacious when the pain state is involving the nervous systemitself, peripheral as well as central. These pain states are oftenreferred to as neuropathic pain. As a final resort clinicians oftenprescribe drugs which are not considered true analgesics but which bytrial and error have been found partly useful. Such agents includetricyclic antidepressants, for example amitriptylin, anticonvulsantslike carbamazepine and gabapentin, and some local anesthetics andantiarrhythmics, especially mexiletine.

[0006] It has surprisingly been found that certain spirooxindolederivatives exhibit good analgesic properties and are particularlyeffective in the treatment of chronic pain.

DISCLOSURE OF THE INVENTION

[0007] It has surprisingly been found that compounds of the Formula I,which are spirooxindole derivatives, are particularly effectiveanalgesic compounds and thereby suitable in the treatment of pain.

[0008] In one aspect, the present invention thus relates to compounds ofthe general Formula I

[0009] or a pharmaceutically acceptable salt thereof, wherein

[0010] R¹ is

[0011] a) H,

[0012] b) substituted or unsubstituted C₁-C₆ alkyl,

[0013] c) C₁-C₆ alkoxy C₂-C₆ alkyl,

[0014] d) C₁-C₆ alkylthio C₂-C₆ alkyl,

[0015] e) halogenated C₁-C₆ alkyl,

[0016] f) aryl C₁-C₆ alkyl,

[0017] g) C₁-C₆ alkenyl, or

[0018] h) C₁-C₆ cycloalkyl C₁-C₂ alkyl;

[0019] R²is

[0020] a) H,

[0021] b) C₁-C₆ alkyl,

[0022] c) C₂-C₄ alkynyl,

[0023] d) halogen,

[0024] e) substituted or unsubstituted carbamoyl,

[0025] f) substituted or unsubstituted carbamoyloxy,

[0026] g) C₁-C₆ alkylcarbonyl,

[0027] h) C₁-C₆ alkoxycarbonyl,

[0028] i) C₁-C₆ alkylcarbonyloxy,

[0029] j) hydroxy-substituted C₁-C₆ alkyl,

[0030] k) cyano,

[0031] l) nitro,

[0032] m) amino,

[0033] n) halogenated C₁-C₆ alkyl,

[0034] o) halogenated C₁-C₆ alkoxy,

[0035] p) halogenated C₁-C₆ alkylthio,

[0036] q) C₁-C₆ alkylsulfinyl,

[0037] r) C₁-C₆ alkylsulfonyl,

[0038] s) C₁-C₄ alkylsulfinylalkyl,

[0039] t) C₁-C₄ alkylsulfonylalkyl,

[0040] u) C₁-C₆ alkylsulfonylamino,

[0041] v) halogenated C₁-C₆ alkylsulfonylamino,

[0042] w) halogenated C₁-C₂ alkylsulfonyloxy,

[0043] x) aminosulfonyl,

[0044] y) aminosulfonyloxy,

[0045] z) aryl,

[0046] aa) heteroaryl,

[0047] bb) arylcarbonyl,

[0048] cc) heteroarylcarbonyl,

[0049] dd) arylsulfinyl,

[0050] ee) heteroarylsulfinyl,

[0051] ff) arylsulfonyl,

[0052] gg) heteroarylsulfonyl, in which any aromatic moiety isoptionally substituted,

[0053] hh) C₁-C₆ alkylcarbonylamino,

[0054] ii) C₁-C₆ alkoxycarbonylamino,

[0055] jj) C₁-C₆ alkyl-thiocarbonyl,

[0056] kk) C₁-C₆ alkoxy-thiocarbonyl,

[0057] ll) formyl, or

[0058] mm)alkoxysulfonylamino;

[0059] R³ is

[0060] a) H,

[0061] b) C₁-C₆ alkyl,

[0062] c) halogen,

[0063] d) C₁-C₆ alkoxy,

[0064] e) halogenated C₁-C₄ alkyl,

[0065] f) halogenated C₁-C₆ alkoxy,

[0066] g) halogenated C₁-C₆ alkylthio,

[0067] h) C₁-C₄ alkylsulfinyl,

[0068] i) C₁-C₄ alkylsulfonyl,

[0069] j) C₁-C₄ alkylsulfinyl C₁-C₆ alkyl,

[0070] k) C₁-C₄ alkylsulfonyl C₁-C₆ alkyl,

[0071] I) C₁-C₄ alkylsulfonylamino,

[0072] m)halogenated C₁-C₄ alkylsulfonylamino,

[0073] n) aminosulfonyl, or

[0074] o) aminosulfonyloxy;

[0075] R⁴ is

[0076] a) H,

[0077] b) C₁-C₄ alkyl, or

[0078] c) halogen;

[0079] R² and R³ may together with the carbon atoms to which they areattached, form a saturated or unsaturated ring, optionally containingone or more further heteroatoms, and/or optionally substituted with oneor more substituents selected from halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy,CF₃, OH, cyano, amino, C₁-C₆ alkyl-NH—, (C₁-C₆ alkyl)₂—N—, CN, NH₂SO₂,NH₂CO—, or C₁-C₆ alkyl-CO—;

[0080] Any amino moiety in R²-R⁴ can optionally be substituted with oneor two C₁ -C₆ alkyl groups which may be part of a ring;

[0081] Ar is

[0082] a) benzene,

[0083] b) pyridine,

[0084] c) thiophene,

[0085] d) pyrazine,

[0086] e) pyrimidine,

[0087] f) oxazole,

[0088] g) thiazole,

[0089] h) pyrrole,

[0090] i) pyrazole, or

[0091] j) furan;

[0092] X is

[0093] a) —NHCO—,

[0094] b) —CONH—,

[0095] c) —NH—SO₂—,

[0096] d) —SO₂NH—,

[0097] e) —OCH₂—,

[0098] f) —NHCH₂—, or

[0099] g) —NHCOCH₂—;

[0100] Y is

[0101] a) —CH₂—,

[0102] b) —CH(C₁-C₆ alkyl)—,

[0103] c) —C(C₁-C₆ alkyl)₂—, or

[0104] d) a single bond;

[0105] Z is

[0106] a) —CH₂CH₂CH₂—,

[0107] b) —CH₂CH₂CH₂CH₂—,

[0108] c) —CH═CHCH₂—,

[0109] d) —CH═CHCH₂CH₂—, or

[0110] e) —CH₂CH═CHCH₂—;

[0111] provided that when X is —NHCOCH₂— then Y cannot be —CH₂—; and

[0112] excluding the racemic compounds wherein Ar is benzene, R²-R⁴ ishydrogen, X is NHCO, Y is a single bond, Z is —CH₂CH₂CH₂—, and R¹ isethyl or n-propyl.

[0113] The pure enantiomers, racemic mixtures and unequal mixtures oftwo enantiomers are within the scope of the invention. It should beunderstood that also all the diastereomeric forms possible are withinthe scope of the invention.

[0114] It will also be appreciated by those skilled in the art, althoughderivatives of compounds of formula I may not possess pharmacologicalactivity as such, they may be administered parenterally or orally andthereafter metabolized in the body to form compounds of the inventionwhich are pharmacologically active. Such derivatives, of which theN-oxide is one example, may therefore be described as “prodrugs”. Allprodrugs of compounds of formula I are included within the scope of theinvention.

[0115] Depending on the process conditions the final products of theFormula I are obtained either in neutral or salt form. Salt formsinclude hydrates and other solvates and also crystalline formpolymorphs. Both the free base and the salts of these end products arewithin the scope of the invention.

[0116] Acid addition salts of the new compounds may in a manner knownper se be transformed into the free base using basic agents such asalkali or by ion exchange. The free base obtained may also form saltswith organic or inorganic acids.

[0117] In the preparation of acid addition salts, preferably such acidsare used which form suitably pharmaceutically acceptable salts. Examplesof such acids are hydrochloric acid, sulfuric acid, phosphoric acid,nitric acid, aliphatic, alicyclic carboxylic or sulfonic acids, aromaticor heterocyclic carboxylic or sulfonic acids, such as formic acid,acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid,malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid,hydroxymaleic acid, pyruvic acid, p-hydroxybenzoic acid, embonic acid,methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid,halogenbensenesulfonic acid, toluenesulfonic acid or naphthalenesulfonicacid. All crystalline form polymorphs are within the scope of theinvention.

[0118] Preferred compounds of the invention are those of Formula Iwherein

[0119] R¹ is

[0120] a) H,

[0121] b) C₁-C₄ alkyl,

[0122] c) C₁-C₄ alkoxy C₁-C₄ alkyl,

[0123] d) C₁-C₄ alkylthio C₁-C₄ alkyl,

[0124] e) fluorinated C₁-C₄ alkyl,

[0125] f) aryl C₁-C₄ alkyl,

[0126] g) C₁-C₄ alkenyl, or

[0127] h) cyclopropylmethyl;

[0128] R² is

[0129] a) H,

[0130] b) C₁-C₄ alkyl,

[0131] c) C₂-C₃ alkynyl,

[0132] d) halogen,

[0133] e) substituted or unsubstituted carbamoyl,

[0134] f) substituted or unsubstituted carbamoyloxy,

[0135] g) C₁-C₃ alkylcarbonyl,

[0136] h) C₁-C₃ alkoxycarbonyl,

[0137] i) C₁-C₃ alkylcarbonyloxy,

[0138] j) hydroxy-substituted C₁-C₃ alkyl,

[0139] k) cyano,

[0140] l) fluorinated C₁-C₃ alkoxy,

[0141] m) fluorinated C₁-C₆ alkylthio,

[0142] n) C₁-C₃ alkylsulfinyl,

[0143] o) C₁-C₃ alkylsulfonyl,

[0144] p) C₁-C₃ alkylsulfinyl C₁-C₆ alkyl,

[0145] q) C₁-C₄ alkylsulfonyl C₁-C₆ alkyl,

[0146] r) C₁-C₃ alkylsulfonylamino,

[0147] s) halogenated C₁-C₃ alkylsulfonylamino,

[0148] t) sulfamoyl,

[0149] u) sulfamoyloxy,

[0150] v) aryl,

[0151] w) heteroaryl,

[0152] x) heteroarylsulfinyl,

[0153] y) arylsulfonyl,

[0154] z) heteroarylsulfonyl, in which any aromatic moiety is optionallysubstituted,

[0155] aa) C₁-C₄ alkylcarbonylamino,

[0156] bb) C₁-C₃ alkoxycarbonylamino,

[0157] cc) C₁-C₃ alkyl-thiocarbonyl, or

[0158] dd) C₁-C₃ alkoxy-thiocarbonyl;

[0159] R³ is

[0160] a) H,

[0161] b) C₁-C₄ alkyl, or

[0162] c) halogen;

[0163] R⁴ is

[0164] a) H,

[0165] b) C₁-C₄ alkyl, or

[0166] c) halogen,

[0167] R² and R³ may together with the carbon atoms to which they areattached, form a saturated or unsaturated ring, optionally containingone or more further heteroatoms, and/or optionally substituted with oneor more substituents selected from halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy,CF₃, OH, cyano, amino, C₁-C₆ alkyl-NH—, (C₁-C₆ alkyl)₂—N—, CN, NH₂SO₂,NH₂CO—, or C₁-C₆ alkyl-CO—;

[0168] Any amino moiety in R²-R⁴ can obtionally be substituted with oneor two C₁-C₆ alkyl groups which may be part of a ring;

[0169] Ar is

[0170] a) benzene,

[0171] b) pyridine,

[0172] c) thiophene,

[0173] d) pyrazine,

[0174] e) pyrimidine,

[0175] f) oxazole,

[0176] g) thiazole,

[0177] h) pyrrole,

[0178] i) pyrazole, or

[0179] j) furan;

[0180] X is

[0181] a) —NHCO—,

[0182] b) —CONH—,

[0183] c) —NH—SO₂—, or

[0184] d) —SO₂NH—;

[0185] Y is

[0186] a) —CH₂—,

[0187] b) —CH(C₁-C₆ alkyl)-,

[0188] c) —C(C₁-C₆ alkyl)₂— or

[0189] d) a single bond;

[0190] Z is

[0191] a) —CH₂CH₂CH₂—,

[0192] b) —CH₂CH₂CH₂CH₂—,

[0193] c) —CH═CHCH₂—,

[0194] d) —CH═CHCH₂CH₂—, or

[0195] e) —CH₂CH═CHCH₂—;

[0196] provided that when X is —NHCOCH₂— then Y cannot be —CH₂—; and

[0197] excluding the racemic compounds wherein Ar is benzene, R²-R⁴ ishydrogen, X is NHCO, Y is a single bond, Z is —CH₂CH₂CH₂—, and R¹ isethyl or n-propyl.

[0198] More preferred compounds of the invention are those of Formula Iwherein

[0199] R¹ is

[0200] a) H,

[0201] b) C₁-C₄ alkyl, or

[0202] c) C₁-C₄ alkoxy C₁-C₄ alkyl;

[0203] R² is

[0204] a) H,

[0205] b) C₁-C₄ alkyl,

[0206] c) halogen,

[0207] d) substituted or unsubstituted carbamoyl,

[0208] e) substituted or unsubstituted carbamoyloxy,

[0209] f) C₁-C₂ alkylcarbonyl,

[0210] g) C₁-C₃ alkoxycarbonyl,

[0211] h) cyano,

[0212] i) fluorinated C₁-C₂ alkoxy,

[0213] j) fluorinated C₁-C₆ alkylthio,

[0214] k) C₁-C₃ alkylsulfinyl,

[0215] l) C₁-C₃ alkylsulfonyl,

[0216] m) C₁-C₂ alkylsulfonylamino,

[0217] n) C₁-C₃ alkylcarbonylamino, or

[0218] o) C₁-C₃ alkoxycarbonylamino;

[0219] R³ is

[0220] a) H,

[0221] b) C₁-C₄ alkyl, or

[0222] c) halogen;

[0223] R⁴ is

[0224] a) H,

[0225] b) C₁-C₄ alkyl, or

[0226] c) halogen;

[0227] R² and R³ may together with the carbon atoms to which they areattached, form a saturated or unsaturated ring, optionally containingone or more further heteroatoms, and/or optionally substituted with oneor more substituents selected from halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy,CF₃, OH, cyano, amino, C₁-C₆ alkyl-NH—, (C₁-C₆ alkyl)₂-N—, CN, NH₂SO₂,NH₂CO—, or C₁-C₆ alkyl-CO—;

[0228] Any amino moiety in R²-R⁴ can optionally be substituted with oneor two C₁-C₆ alkyl groups which may be part of a ring;

[0229] Ar is

[0230] a) benzene,

[0231] b) pyridine,

[0232] c) thiophene,

[0233] d) pyrazine,

[0234] e) pyrimidine,

[0235] f) oxazole,

[0236] g) thiazole,

[0237] h) pyrrole,

[0238] i) pyrazole, or

[0239] j) furan;

[0240] X is

[0241] a) —NHCO—,

[0242] b) —CONH—,

[0243] c) —NH—SO₂—, or

[0244] d) —SO₂NH—;

[0245] Y is

[0246] a) —CH₂—,

[0247] b) —CH(C₁-C₆ alkyl)-,

[0248] c) —C(C₁-C₆ alkyl)₂-, or

[0249] d) a single bond;

[0250] Z is

[0251] a) —CH₂CH₂CH₂—,

[0252] b) —CH₂CH₂CH₂CH₂—,

[0253] c) —CH═CHCH₂—,

[0254] d) —CH═CHCH₂CH₂—, or

[0255] e) —CH₂CH═CHCH₂—;

[0256] excluding the racemic compounds wherein Ar is benzene, R²-R⁴ ishydrogen, X is NHCO, Y is a single bond, Z is —CH₂CH₂CH₂—, and R¹ isethyl or n-propyl.

[0257] Particularly preferred compounds of the invention are those ofFormula I wherein

[0258] R¹ is H;

[0259] R² is

[0260] a) H,

[0261] b) C₁-C₄ alkyl, or

[0262] c) halogen;

[0263] R³ is

[0264] a) H,

[0265] b) C₁-C₄ alkyl, or

[0266] c) halogen;

[0267] R⁴ is

[0268] a) H,

[0269] b) C₁-C₄ alkyl, or

[0270] c) halogen;

[0271] Ar is

[0272] a) benzene, or

[0273] b) pyridine;

[0274] X is

[0275] a) —NHCO—,

[0276] b) —CONH—, or

[0277] c) —NH—SO₂—;

[0278] Y is a single bond;

[0279] Z is

[0280] a) CH₂CH₂CH₂—, or

[0281] b) —CH═CHCH₂—,

[0282] excluding the racemic compounds wherein Ar is benzene, R²-R⁴ ishydrogen, X is NHCO, Y is a single bond, Z is —CH₂CH₂CH₂—, and R¹ isethyl or n-propyl.

[0283] It has furthermore surprisingly been found that the(S)-enantiomers of the compounds of formula I possess a higher analgesicactivity than the (R)-enantiomers and are thus preferred for therapeuticuse before the latter and the racemic mixtures.

[0284] Another aspect of the present invention is therefore theS-enantiomer, referring to the marked spirocarbon, of the compounds ofthe general Formula I

[0285] or a pharmaceutically acceptable salt thereof, as defined above.

[0286] The following definitions shall apply throughout thespecification and the appended claims:

[0287] The term “C₁-C₆ alkyl” denotes a cyclic or linear, straight orbranched, substituted or unsubstituted alkyl group having from 1 to 6carbon atoms. Examples of said alkyl include, but is not limited tomethyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl,cyclohexyl, and cyclopentyl.

[0288] The term “C₁-C₆ alkoxy” denotes a group O-alkyl, wherein alkyl isas defined above.

[0289] The terms “C₁-C₄ alkyl”, “C₁-C₃ alkyl”, “C₁-C₂ alkyl” have thecorresponding meaning as “C₁-C₆ alkyl”.

[0290] The term “halogen” includes fluoro, chloro, bromo and iodogroups.

[0291] The term “aryl” denotes a substituted or unsubstituted C₆-C₁₄aromatic hydrocarbon and includes, but is not limited to, benzene,naphtalene, indene, antracene, fenantrene, and fluorene.

[0292] The term “substituted” denotes e.g. an Cl-C₆ alkyl, C₁-C₆alkylaryl or aryl group as defined above which is substituted by one ormore alkyl, alkoxy, halogen, amino, thiol, nitro, hydroxy, acyl, cyanoor oxo groups.

[0293] The term “heteroatoms” denotes a nitrogen, oxygen, sulfur, or aphosphorous atom.

[0294] Most preferred compounds according to the invention are listed inthe following table. The compounds can be in neutral form or in saltform as earlier indicated, for example in hydrochloride form.

[0295] 5-Fluorospiro[indolin-3,3′-piperidin]-2-one

[0296] 5-Fluoro-1′-isopropylspiro[indolin-3,3′-piperidin]-2-one

[0297] (R)-5-Fluoro-1′-isopropylspiro[indolin-3,3′-piperidin]-2-one

[0298] (S)-5-Fluoro-1′-isopropylspiro[indolin-3,3′-piperidin]-2-one

[0299] 5,7-Difluorospiro[indolin-3,3′-piperidin]-2-one acetate

[0300] 5,7-Difluoro-1′-isopropylspiro[indolin-3,3′-piperidin]-2-one

[0301] (S)-5,7-Difluoro-1′-isopropylspiro[indolin-3,3′-piperidin]-2-one

[0302] 1′,5-Dimethylspiro[indolin-3,3′-piperidin]-2-one

[0303] 5-Methyl-1′-isopropyl-spiro[indolin-3,3′-piperidin]-2-one

[0304] 6-Methyl-1′-isopropyl-spiro[indolin-3,3′-piperidin]-2-one

[0305] 4-Methylspiro[indolin-3,3′-piperidin]-2-one

[0306] 4-Methyl-1′-isopropylspiro[indolin-3,3′-piperidin]-2-one

[0307] 4-Methyl-1′-propylspiro[indolin-3,3′-piperidin]-2-one

[0308] 7-Fluorospiro[indolin-3,3′-(1,2,3,6-tetrahydropyridin)]-2-one

[0309] (S)-(+)-7-Fluorospiro[indolin-3,3′-piperidin]-2-one

[0310] Spiro[indolin-3,3′-piperidin]-2-one

[0311] 1′-Ethylspiro[indolin-3,3′-piperidin]-2-one

[0312] 1′-Propyl-spiro[indolin-3,3′-piperidin]-2-one

[0313] 1′-Isopropylspiro[indolin-3,3′-piperidin]-2-one

[0314] 1′-Allylspiro[indolin-3,3′-piperidin]-2-one

[0315] 1′-Cyclopropylmethylspiro[indolin-3,3′-piperidin]-2-one

[0316] 1′-Butylspiro[indolin-3,3′-piperidin]-2-one

[0317] 1′-s-Butylspiro[indolin-3,3′-piperidin]-2-one

[0318] (S)-(+)-1′-Propylspiro[indolin-3,3′-piperidin]-2-one

[0319] 1′-Propylspiro[4-azaindolin-3,3′-piperidin]-2-one

[0320] 1′-Butylspiro[4-azaindolin-3,3′-piperidin]-2-one

[0321] 1′-sec-Butylspiro[4-aza-indolin-3,3′-piperidin]-2-one

[0322] 1′-Propyl-5-chlorospiro[7-aza-indolin-3,3′-piperidin]-2-one

[0323] 1′-Propylspiro[7-azaindolin-3,3′-piperidin]-2-one

[0324] 1′-Propyl-6-methylspiro[7-azaindolin-3,3′-piperidin]-2-one

[0325] 1′-Propylspiro[isoindolin-3,3′-piperidin]-1-one hydrochloride

[0326] 1′-Isopropylspiro[indoline-3,3′-piperidine]hydrochloride

[0327]2,3-Dihydro-1H-1′-Propylspiro[thieno[3,2-b]pyrrol-3,3′-piperidin]-2-one

[0328]2,3,1′,2′,3′,6′-Hexahydro-1H-spiro[thieno[3,2-b]pyrrol-3,3′-pyridin]-2-one

[0329]2,3,1′,2′,3′,6′-Hexahydro-1H-spiro[5,8-diazaindol-3,3′-pyridin]-2-one

[0330] 1′,2′,3′4′-Tetrahydrospiro[indolin-3,3′-(7H)-azepin]-2-one

[0331] 1′,2′,3′4′-Tetrahydrospiro[7-azaindolin-3,3′-(7H)-azepin)-2-one

[0332]1′-Ethyl-1′,2′,3′4′-tetrahydrospiro[4-azaindolin-3,3′-(7H)-azepin)-2-one

[0333] 1′-Propylspiro[indolin-3,3′-piperidin]-2-one 1′-oxide

[0334] Further most preferred compounds according to the invention:

[0335] Also these compounds can be in neutral form or in salt form asearlier indicated.

[0336](S)-5-Chloro-7-fluorospiro[indolin-3,3′-(1,2,3,6-tetrahydropyridin)]-2-one

[0337](S)-5-Methylspiro[7-azaindoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-one

[0338](S)-5,6-Dimethylspiro[7-azaindoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-one

[0339](S)-6-Methylspiro[7-azaindoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-one

[0340](S)-5-Chlorospiro[7-azaindoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-one

[0341](S)-5,7-Difluorospiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-one

[0342](S)-7-Chlorospiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-one

[0343](S)-7-Fluoro-5-methylspiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-one

[0344](S)-5-Methoxyspiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-one

[0345] (S)-5-Chlorospiro[indoline-3,3′-piperidin]-2-one

Preparation

[0346] The present invention also provides the following processes forthe preparation of compounds of the general Formula I. The compounds ofthe present invention can be prepared by methods known in the art usingcommercially available, or readily prepared, starting materials. Manyuseful methods for synthesis of oxindoles are reviewed by G. M. Karp inOrg. Prep. Proced. Int. 1993, 25, 481-513, which is incorporated hereinby reference.

[0347] It is to be understood that certain functional groups mayinterfere with other reactants or reagents under the reaction conditionsand therefore may need temporary protection. The use of protectinggroups is described in ‘Protective Groups in Organic Synthesis’, 2ndedition, T. W. Greene & P. G. M. Wutz, Wiley-Interscience (1991).

[0348] Process A

[0349] A process for manufacture of compounds with the general Formula Icomprises the following steps:

[0350] a) Compounds of Formula IV

[0351] wherein L is a halogen or a trifluoromethylsulfonyloxy group, Ar,R²-R⁴ are as defined in Formula I, or can be converted into such groupslater in the synthesis sequence, is coupled with a compound of thegeneral Formula II, or a corresponding lower alkyl ester, e.g. methyl orethyl ester,

[0352] wherein R¹ is as defined for Formula I or is a nitrogenprotecting group, e.g. a Boc group, to give a compound of the generalFormula VII

[0353] b) The resulting amide of the general Formula VII is thencyclized using Heck reaction conditions with palladium as a catalyst orsometimes under radical generating conditions to give, after optionalremoval of protecting groups, a compound of the general formula I

[0354] When the above formed spiro compound contains a double bond thismay be hydrogenated over a metal catalyst to give the correspondingsaturated compound, or by other methods well known to those skilled inthe art. The product is thereafter deprotected, if necessary, or thecyclized protected intermediate compound may be further reacted with,for example organometallic reagents, to give new compounds of theinvention in which an alkyl or alkynyl group is substituted for abromine or an aryl- or alkylsulfonyloxy group.

[0355] Process B

[0356] a) Compounds of Formula IV

[0357] wherein Ar, R²-R⁴, Y are as defined in Formula I, and X is —NHCO—or —NH—SO₂ are alkylated with a compound of the general Formula IX

[0358] wherein Z is as defined in Formula I, L is a bromine, iodine,aryl or alkylsulfonyloxy group, e.g. trifluoromethylsulfonyloxy group, Ais oxygen or nitrogen, and PG is a suitable protecting group or, when Ais nitrogen, equals R¹ of Formula I, to give compounds of the generalformula XII

[0359] wherein Ar, R²-R⁴, and Z are as defined in Formula I, X is—NHCO—, or —NH—SO₂—, A is oxygen or nitrogen and PG is a suitableprotecting group or, when A is nitrogen, equals R¹ of Formula I.

[0360] b) An optional transformation step is performed when A is oxygen,wherein the oxygen function is converted into the corresponding aminofunction by methods well known in the art. One suitable way ofaccomplishing this conversion is to remove the protecting group togenerate the corresponding primary alcohol, which is thereafterconverted into a suitable leaving groups, e.g. a tosylate group. Theleaving group is thereafter displaced by a suitable amino nucleophile togive a compound of the general formula XII, wherein A is nitrogen.

[0361] c) Compounds of the general formula XII can thereafter and afteroptional removal of protecting groups be cyclized to the spiro system togive compounds of the formula I under standard Mannich conditions.

[0362] Process C

[0363] a) Compounds of the general Formula III

[0364] wherein Ar, R¹-R⁴ are as defined in Formula I or R¹ is a benzylicprotecting group, are oxidised into compounds of the general Formula VI,

[0365] wherein Ar, R¹-R⁴ are as defined in Formula I or R¹ is a benzylicprotecting group, as is described in Kornet and Thio, Journal ofMedicinal Chemistry 1976, 19, 892-8 or as referred to in the previouslymentioned review by Karp.

[0366] c) Compounds of the general Formula VI are thereafter cyclizedunder standard Mannich reaction conditions to give a compound of thegeneral Formula I.

[0367] Process D

[0368] a) Compounds of the general Formula V

[0369] wherein Ar, R²-R⁴, X and Y are as defined in Formula I and PG isan amino protecting group, is ring-closed using a ruthenium or molybdenecomplex as a catalyst under standard reaction conditions to givecompounds of the general formula VIII

[0370] This metathesis reaction is described in more detail in thereview by Grubbs, R. H. and Chang, S. Tetrahedron 1998, 54, 4413-50.

[0371] The intermediate V may be prepared by methods known to the oneskilled in the art, for example by alkylation of the intermediate IVwith e.g. allyl bromide followed by a Mannich reaction with a secondaryamine to give a compound of the general formula Va, as is schematicallyshown below.

[0372] In process B and C the amino protecting group used is preferablyan easily removable group, for example groups belonging to thearylmethyl class which can be readily removed by hydrogenolysis, thusreleasing the secondary amine of formula I (R¹═H). Said compound can beconverted to a tertiary amine, by alkylating methods well known in theart. Other suitable protective groups that are described in the organicchemical literature is, for example, an allyl carbamate or a4-methoxybenzyl group.

[0373] Many interconversions of the R² and R³ groups are also evident toone skilled in the art.

[0374] Compounds of the general formula I prepared in this way areracemic. As is well known in the art resolution of the two enantiomerscan be conveniently achieved by classical crystallization methods byusing a chiral acid such as L- or D-ditoluoyltartaric acid or (+) or(−)-1-camphorsulfonic acid in a suitable solvent such as acetone, water,alcohol, ethyl acetate or their mixture. Another method to achieve thesame goal is to separate the enantiomers by chromatography on a chiralcolumn such as Chiralcel OD or Kromasil TBB which are commerciallyavailable. A further well known means to obtain pure enantiomers is bypreparing a derivative of a racemic intermediate, for example an amideof a secondary amine, with an enantiomerically pure acid and thenseparating the so formed diastereomers by crystallization or bychromatography.

Medical Use

[0375] In a further aspect, the present invention relates to compoundsof the formula I for use in therapy, in particular for use in thetreatment of pain. The invention also provides the use of a compound ofthe formula I in the manufacture of a medicament for the treatment ofpain.

[0376] The novel compounds of the present invention are useful intherapy, especially for the treatment and/or prophylaxis of pain ofwidely different origins and causes and include acute as well as chronicpain states. Examples are pain caused by chemical, mechanical,radiation, thermal, infectious or inflammatory tissue trauma or cancer,postoperative pain, headache and migraine, various arthritic andinflammatory conditions such as osteo and rheumatoid arthritis,myofascial and low back pain.

[0377] Also neuropathic conditions of central or peripheral origin canbe treated or prevented with the compounds of the invention. Examples ofthese pain conditions are trigeminal neuralgia, postherpetic neuralgia(PHN), diabetic mono/poly neuropathy, nerve trauma, spinal cord injury,central post stroke, multiple sclerosis and Parkinson's disease. Otherpain states of visceral origin such as caused by ulcer, dysmenorrhea,endometriosis, IBS, dyspepsia etc. can also be treated or prevented withthe compounds of the invention. The compounds of the invention areuseful as therapeutic agents in disease states with inappropriateneuronal activity or in neuroprotection for example as anticonvulsantsin epilepsy, in the treatment of itch, tinnitus, Parkinson's disease,multiple sclerosis, amyotrophic lateral sclerosis (ALS), Alzheimer,stroke, cerebral ischaemia, traumatic brain injury, Huntingdon's chorea,schizophrenia, obsessive compulsive disorders (OCD), neurologicaldeficits associated with AIDS, sleep disorders (including circadianrhythm disorders, insomnia & narcolepsy), tics (e.g. Tourette'ssyndrome), and muscular rigidity (spasticity).

[0378] A primary aim of the invention is to use compounds of the formulaI for oral treatment of neuropathic or central pain states.

[0379] The compounds of the invention are also useful for treatment ofeffects associated with withdrawal from substances of abuse such ascocaine, nicotine, alcohol and benzodiazepines.

[0380] In a further aspect the invention provides the use of a compoundof formula I, or a pharmaceutically acceptable salt or solvate, thereofas a therapeutic agent, in particular for the treatment and/orprophylaxis of anxiety, mania, depression, panic disorders and/oraggression.

[0381] The typical daily dose of the active substance varies within awide range and will depend on various factors such as for example theindividual requirement of each patient, the route of administration andthe disease. In general, the dosages will be in the range of 0.1 to 1000mg per day of active substance.

Pharmaceutical Formulations

[0382] In yet a further aspect, the invention relates to pharmaceuticalcompositions containing at least one compound of the present invention,or a pharmaceutically acceptable salt thereof, as active ingredient.

[0383] For clinical use, the compounds of the invention are formulatedinto pharmaceutical formulations for oral, intravenous, subcutaneous,tracheal, bronchial, intranasal, pulmonary, transdermal, buccal, rectal,parenteral or other mode of administration. The pharmaceuticalformulation contains a compound of the invention in combination with oneor more pharmaceutically acceptable ingredients. The carrier may be inthe form of a solid, semi-solid or liquid diluent, or a capsule. Thesepharmaceutical preparations are a further object of the invention.Usually the amount of active compounds is between 0.1-95% by weight ofthe preparation.

[0384] In the preparation of pharmaceutical formulations containing acompound of the present invention the compound selected may be mixedwith solid, powdered ingredients, such as lactose, saccharose, sorbitol,mannitol, starch, amylopectin, cellulose derivatives, gelatin, oranother suitable ingredient, as well as with disintegrating agents andlubricating agents such as magnesium stearate, calcium stearate, sodiumstearyl fumarate and polyethylene glycol waxes. The mixture may then beprocessed into granules or pressed into tablets.

[0385] Soft gelatine capsules may be prepared with capsules containing amixture of the active compound or compounds of the invention, vegetableoil, fat, or other suitable vehicle for soft gelatine capsules. Hardgelatine capsules may contain granules of the active compound. Hardgelatine capsules may also contain the active compound in combinationwith solid powdered ingredients such as lactose, saccharose, sorbitol,mannitol, potato starch, cornstarch, amylopectin, cellulose derivativesor gelatine.

[0386] Dosage units for rectal administration may be prepared (i) in theform of suppositories which contain the active substance mixed with aneutral fat base; (ii) in the form of a gelatine rectal capsule whichcontains the active substance in a mixture with a vegetable oil,paraffin oil or other suitable vehicle for gelatine rectal capsules;(iii) in the form of a ready-made micro enema; or (iv) in the form of adry micro enema formulation to be reconstituted in a suitable solventjust prior to administration.

[0387] Liquid preparations may be prepared in the form of syrups orsuspensions, e.g. solutions or suspensions containing the activeingredient and the remainder consisting, for example, of sugar or sugaralcohols and a mixture of ethanol, water, glycerol, propylene glycol andpolyethylene glycol. If desired, such liquid preparations may containcoloring agents, flavouring agents, preservatives, saccharine andcarboxymethyl cellulose or other thickening agents. Liquid preparationsmay also be prepared in the form of a dry powder to be reconstitutedwith a suitable solvent prior to use.

[0388] Solutions for parenteral administration may be prepared as asolution of a compound of the invention in a pharmaceutically acceptablesolvent. These solutions may also contain stabilizing ingredients,preservatives and/or buffering ingredients. Solutions for parenteraladministration may also be prepared as a dry preparation to bereconstituted with a suitable solvent before use.

[0389] The typical daily dose of the active substance varies within awide range and will depend on various factors such as for example theindividual requirement of each patient, the route of administration andthe disease. In general, oral and parenteral dosages will be in therange of 0.1 to 1000 mg per day of active substance.

[0390] The compounds according to the present invention can also be usedin formulations, together or in combination for simultaneous, separateor sequential use, with other active ingredients, such as

[0391] a) opioid analgesics, for example morphine, ketobemidone orfentanyl

[0392] b) analgesics of the NSAID class, for example ibuprofene,selecoxib or acetylsalicylic acid

[0393] c) amino acids such as gabapentin or pregabalin

[0394] d) analgesic adjuvants such as amitriptyline or mexiletine

[0395] e) NMDA antagonists for example ketamine or dextrometorfan

[0396] f) sodium channel blocking agents for example lidocaine

[0397] g) anticonvulsants, for example carbamazepine or lamotrigine

[0398] h) cannabinoids

Intermediates

[0399] A further aspect of the invention is new intermediate compoundswhich are useful in the synthesis of compounds according to theinvention.

[0400] Thus, the invention includes

[0401] (a) a compound of the formula XI

[0402] wherein Ar, R¹-R⁴ and X are as defined for Formula I, L isbromide, iodide, or triflate and R¹ may also be a nitrogen protectinggroup, such as a alkoxycarbonyl or a benzyl group, of whicht-butoxycarbonyl is especially preferred and X, when containing anitrogen atom, may optionally be substituted with a t-butoxycarbonylgroup.

EXAMPLES 1. Preparation of Compounds of the Invention

[0403] All chemicals and reagents were used as received from suppliers.¹³C and ¹H nuclear magnetic resonance (NMR) spectra were recorded on aVarian Unity 400 (400 MHz) spectrometer. Silica gel chromatography (SGC)was carried out on silica gel 60 (230-400 mesh). Mass spectrometry (MS)was carried out in the positive thermospray (TSP+), chemical ionization(CI), or in the electron impact (EI) modes.

[0404] Other abbreviations: Boc, t-butyloxycarbonyl; DCM,dichloromethane; EtOAc ethyl acetate.

Example 1 5-Fluorospiro[indoline-3,3′-piperidin]-2-one hydrochloride

[0405] STEP A. t-Butyl3-(2-bromo-4-fluorophenylcarbamoyl)-1,2,5,6-tetrahydropyridine-1-carboxylate.2-Bromo-4-fluoroaniline (2.53 g, 13.3 mmol) was dissolved indichloromethane (30 mL) under N₂-atmosphere and trimethylaluminium (2.0M in hexanes, 8 mL) was added. The solution was stirred during 15minutes, whereupon a solution of5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-t-butyl ester 3-methylester (3.67 g, 13.3 mmol) in DCM (20 mL) was added. The mixture wasrefluxed overnight and saturated NaHCO₃ was carefully added followed byDCM. The aqueous phase was extracted with DCM. The crude product waspurified by chromatography on silica gel using a gradient of toluene toacetonitrile to give the title compound (4.55 g) in 86 % yield as anyellow oil. R_(f) 0.54 (toluene/acetonitrile 3:1). MS(TSP+) m/z calcdfor [M+NH₄]⁺: 416, 418, observed: 416, 418.

[0406] STEP B. t-Butyl3-[(2-bromo-4-fluorophenyl)-(t-butoxycarbonyl)-carbamoyl]-1,2,5,6-tetrahydropyridine-1-carboxylate.The product from STEP A (3.51 g) was dissolved in dry acetonitrile underN₂-atmosphere. 4-Dimethylaminopyridine (120 mg, 0.98 mmol) anddi-t-butyl dicarbonate (2.08 g, 9.53 mmol) were added. After reactionovernight the acetonitrile was stripped off and the residue wasdissolved in diethyl ether (200 mL). The ethereal phase was extractedwith 0.2 M aqueous solution of citric acid (3×50 mL) and then withsaturated NaHCO₃ (3×50 mL). The product was purified by chromatographyon silica gel using a gradient of toluene to acetonitrile to give thetitle compound in 91% yield as a yellow oil. MS(TSP+) m/z observed: 516,518 (20%).

[0407] STEP C.Di-t-butyl5-fluoro-2-oxospiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-1,1′-dicarboxylate.The amide from STEP B (994 mg, 1.99 mmol) was dissolved in acetonitrile(20 mL) under N₂-atmosphere. Triphenylphosphine (133 mg, 0.51 mmol),triethylamine (0.42 mL, 3 mmol) and palladium acetate (50 mg, 0.22 mmol)were added. The mixture was refluxed for 5 days under N₂-atmosphere. Thecrude product was purified by chromatography on silica gel and elutedwith a gradient of toluene to acetonitrile to give the title compound(604 mg) in 73% yield as a yellow oil. R_(f) 0.58 (toluene/acetonitrile3:1). MS(CI, NH₃) m/z 436.

[0408] STEP D. t-Butyl5-fluoro-2-oxospiro[indoline-3,3′-(1,2,3,6-tetrahydro-pyridin)]-1′-carboxylate.The compound from STEP A (1.00 g, 2.50 mmol) was cyclised to the titlecompound (382 mg) in 48% yield following the same procedure as describedin STEP C. MS (TSP+) m/z [M+H]⁺: 319.

[0409] STEP E. Di-t-butyl5-fluoro-2-oxospiro[indoline-3,3′-piperidin]-1,1′-dicarboxylate. Theproduct from STEP C (590 mg, 1.41 mmol) was hydrogenated in absoluteethanol (20 mL) using PtO₂ and H₂ (3.5 atm) for 2 days. The reactionmixture was filtered using 00H-filter paper and the solvent wasevaporated to give the title compound (563 mg) in 95% yield. MS (TSP+)m/z calcd for [M−BOC+H]⁺: 321, observed: 321.

[0410] STEP F. t-Butyl5-fluoro-2-oxospiro[indoline-3,3′-piperidin]-1′-carboxylate. The productfrom STEP D (344 mg, 1.08 mmol) was transformed to the title compound(295 mg) following the same procedure as described in STEP E. MS (TSP+)m/z [M+H]⁺: 321.

[0411] STEP G. 5-Fluorospiro[indoline-3,3′-piperidin]-2-onehydrochloride. The product from STEP E. (563 mg, 1.34 mmol) wasdissolved in methanol (10 mL) and was treated with HCI (2.5 M etherealsolution, 5 mL). The solvents were stripped off to give the product (341mg) in 99% yield as a white solid. The same procedure was also appliedto the product from STEP F. MS(TSP+) m/z calcd for [M−Cl]⁺: 221,observed: 221.

Example 2 5-Fluoro-1′-isopropylspiro[indoline-3,3′-piperidin]-2-onehydrochloride

[0412] The amine from EXAMPLE 1 was alkylated using PROCEDURE 1, MethodA. The crude product was purified by chromatography on silica gel usinga gradient of toluene to acetonitrile/triethyl amine 100:5 to give theamine in 64% yield. ¹³C-NMR (CDCl₃) δ 182.3, 158.5 (d, J236 Hz), 136.4,135.9, 114.4 (d, J26 Hz), 113.4 (d, J25 Hz), 109.8, 54.8, 53.9, 49.2,48.9, 32.0, 21.7, 18.0, 17.6. It was converted to the title compoundwith HCl in ether. MS(TSP+) m/z calcd for [M−Cl]⁺: 263, observed: 263.

Example 3 (R)-5-Fluoro-1′-isopropylspiro[indoline-3,3′-piperidin]-2-onehydrochloride.

[0413] 5-Fluoro-1′-isopropyl-spiro[indoline-3,3′-piperidin]-2-one (215mg) from EXAMPLE 2 was chromatographed on a Kromasil TBB column elutingwith hexane/1-propanol/1-butanol 99:0.5:0.5. The pure stereoisomer (72mg) was collected as the first eluting peak in 67% yield and anenantiomeric excess of 97%. [α]₅₈₉ ²²−1.18°, [α]₃₆₅ ²²−10.0° (c 1.01,CHCl₃). It was converted to the title compound. [α]₅₈₉ ²²−6.93° (c 1.01,MeOH).

Example 4 (S)-5-Fluoro-1′-isopropylspiro[indoline-3,3′-piperidin]-2-one.

[0414] 62 mg was collected from EXAMPLE 3 as the second enantiomer in58% yield and an enantiomeric excess of 99%. [α]₅₈₉ ²²+1.05°, [α]₃₆₅²²+9.32° (c 1.03, CHCl₃). It was converted to the hydrochloride. [α]₅₈₉²²+6.22°, (c 1.03, MeOH).

Example 5 5,7-Difluorospiro[indoline-3,3′-piperidin]-2-one acetate

[0415] STEP A. 1-Benzyl-N-(2-bromo-4,6-difluorophenyl)-1,2,5,6-tetrahydropyridine-3-carboxamide.The title compound was prepared from 2-bromo-4,6-difluoroaniline and1-benzyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester asdescribed in EXAMPLE 1. R_(f) 0.53 (toluene/acetonitrile/tri-ethyl amine10:10:1).

[0416] STEP B.5,7-Difluoro-1′-benzylspiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-one.

[0417] The product from STEP A was cyclized as described in EXAMPLE 1.

[0418] STEP C. 5,7-Difluorospiro[indoline-3,3′-piperidin]-2-one acetate.The product from STEP B was hydrogenated in glacial acetic acid (20 mL)using 10% Pd/C and H₂ (3.5 atm) for 24 hours. The title compound wasobtained in 86% yield as a crystalline solid. MS(TSP+) m/z calcd for[M−AcO]⁺: 239, observed: 239.

Example 6 5,7-Difluoro-1′-isopropylspiro[indoline-3,3′-piperidin]-2-onehydrochloride

[0419] The amine from the previous EXAMPLE was alkylated as described inEXAMPLE 2 to give the free amine of the title compound in 58% yield as awhite solid. ¹³C-NMR (CDCl₃) δ 180.3, 157.9 (d, J240 Hz), 146.0 (d, J244Hz), 137.8, 123.2 (d, J11 Hz), 110.3 (d, J25 Hz), 102.6 (dd, J21, 21Hz), 54.9, 53.9, 49.4, 48.7, 32.1, 21.6, 18.1, 17.6. It was converted tothe hydrochloride. MS(TSP+) m/z calcd for [M−Cl]⁺: 281, observed: 281.

EXAMPLE 7(S)-5,7-Difluoro-1′-isopropylspiro[indoline-3,3′-piperidin]-2-onehydrochloride

[0420] STEP A. Chromatography.5,7-Difluoro-1′-isopropyl-spiro[indoline-3,3′-piperidin]-2-one (231 mg)from the preceding example was chromatographed on a Kromasil TBB columneluting with hexane/1-propanol/1-butanol 98:1:1.(R)-5,7-Difluoro-1′-isopropylspiro[indoline-3,3′-piperidin]-2-one (94mg) was collected as the first enantiomer in 81% yield and anenantiomeric excess of 97.6%. -0.30° (c 1.00, CHCl₃).(S)-5,7-Difluoro-1′-isopropyl-spiro[indoline-3,3′-piperidin]-2-one wascollected as the second peak (92 mg) in 80% yield and an enantiomericexcess of 98.4%, +0.12° (c 1.00, CHCl₃).

[0421] STEP B.(S)-5,7-Difluoro-1′-isopropylspiro[indoline-3,3′-piperidin]-2-onehydrochloride. The (S)-enantiomer from STEP A was converted to thehydrochloride to give the title compound as a white solid, 6.20° (c1.00, MeOH).

Example 8 1′,5-Dimethylspiro[indoline-3,3′-piperidin]-2-onehydrochloride.

[0422] The title compound was prepared from 2-Bromo-4-methyl-aniline andarecholine hydrobromide as described in EXAMPLE 1. MS(TSP+) m/z calcdfor [M−Cl]⁺: 231, observed: 231

Example 9 5-Methyl-1′-isopropyl-spiro[indoline-3,3′-piperidin]-2-onehydrochloride

[0423] The title compound was obtained from 2-bromo-4 methyl-aniline andmethyl N-benzyl-1,2,3,6-tetrahydropyridin-3-carboxylate as described inEXAMPLE 1. MS(TSP+) m/z calcd for [M−Cl]⁺: 259, observed: 259.

Example 10 6-Methyl-1′-isopropyl-spiro[indoline-3,3′-piperidin]-2-onehydrochloride

[0424] The title compound was obtained as described in EXAMPLE 9starting with 2-iodo-5-methyl-aniline. MS(TSP+) m/z calcd for [M−Cl]⁺:259, observed: 259

Example 116-Trifluoromethyl-1′-isopropyl-spiro[indoline-3,3′-piperidin]-2-onehydrochloride

[0425] The title compound was obtained as described in EXAMPLE 9starting with 3-amino-4bromo-benzotrifluoride. MS(TSP+) m/z calcd for[M+H]⁺: 439, 441, observed: 439, 441.

Example 12 4-Methylspiro[indoline-3,3′-piperidin]-2-one hydrochloride

[0426] The title compound was obtained as described in EXAMPLE 9starting with 2-Bromo-3-methylaniline. [M]⁺: 217, observed: 217. It wasconverted to the hydrochloride.

Example 13 4-Methyl-1′-isopropylspiro[indoline-3,3′-piperidin]-2-onehydrochloride

[0427] The compound from the previous EXAMPLE was alkylated to the titlecompound using PROCEDURE 1, Method A. ¹³C-NMR (CDCl₁₃): δ 181.4, 141.0,134.6, 130.4, 127.9, 125.2, 107.5, 61.0, 56.2, 54.1, 53.7, 48.6, 28.3,21.2, 19.9, 19.5, 11.9.

Example 14 4-Methyl-1′-propylspiro[indoline-3,3′-piperidin]-2-onehydrochloride

[0428] The compound from EXAMPLE 12 was alkylated to the title compound.¹³C-NMR of the base (CDCl₃): δ 181.5, 141.1, 134.7, 130.8, 127.8, 125.2,107.5, 54.6, 50.9, 49.7, 28.6, 21.6, 19.8, 19.3, 15.9. MS(TSP+) m/zcalcd for [M−Cl]⁺: 259, observed: 259.

Example 15 (S)-(+)-4-Methylspiro[indoline-3,3′-piperidin]-2-onehydrochloride

[0429] The title compound was prepared by separating the N-bocylatedcompound from EXAMPLE 12 on a Kirasil TBB column and removing the Bocgroup from the collected product in 1M HCl in methanol. [M−Cl]⁺: 217,observed: 217.

Example 16(S)-(+)-4-Methyl-1′-propylspiro[indoline-3,3′-piperidin]-2-onehydrochloride

[0430] The compound from the previous EXAMPLE was alkylated to the titlecompound using PROCEDURE 1, Method B.

Example 177-Fluorospiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-onehydrochloride

[0431] The title compound was prepared from 2-bromo-6-fluoroanilinefollowing the steps described in EXAMPLE 16 but deprotecting thedibocylated unsaturated intermediate. [M−Cl]⁺: 219, observed: 219.

Example 18 (S)-(+)-7-Fluorospiro[indoline-3,3′-piperidin]-2-onehydrochloride

[0432] The title compound was prepared by separating the N-bocylatedprecursor on a Kirasil TBB column and removing the Boc group from thecollected product in 1M HCl in methanol. [M−Cl]⁺: 219, observed: 219.

Example 19 Spiro[indoline-3,3′-piperidin]-2-one hydrochloride

[0433] STEP A. t-Butyl5-(2-bromophenylcarbamoyl)-1,2,5,6-tetrahydropyridin-1-carboxylate.2-Bromaniline was amidated to the title compound as described inEXAMPLE 1. MS(TSP+) m/z calcd for [M+NH₄]⁺: 398, 400, observed: 398,400.

[0434] STEP B. t-Butyl3-[(2-bromophenyl)-(t-butoxycarbonyl)-carbamoyl]-1,2,5,6-tetrahydropyridine-1-carboxylate.The compound from STEP A was bocylated to the title compound bydissolving in DCM and add di-tert-butyldicarbonate (1.2 equiv.),triethylamine (1.2 equiv.) and dimethylaminopyridine (0.07 equiv).MS(TSP+) m/z calcd for [M+NH₄]⁺: 498, 500, observed: 498, 500.

[0435] STEP C. Di-t-butyl2-oxospiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-1,1′-dicarboxylate.Obtained according to EXAMPLE 1, STEP C.

[0436] STEP D. Di-t-butyl2-oxospiro[indoline-3,3′-piperidin]-1,1′-dicarboxylate. Obtainedaccording to EXAMPLE 1, STEP D.

[0437] STEP E. Spiro[indoline-3,3′-piperidin]-2-one hydrochloride. Thecompound from the previous step was deprotected by dissolving in 1M HClin methanol and stirring for 1 hour. Evaporation of solvents gave thetitle compound. ¹³C-NMR (d₄-MeOH): 180.6, 140.5, 129.5, 129.2, 122.8,122.7, 110.5, 47.4, 43.7, 30.0, 23.5, 17.4 ppm

Example 20 1′-Ethylspiro[indoline-3,3′-piperidin]-2-one

[0438] The compound was prepared according to PROCEDURE 1, Method A byreaction with spiro[indoline-3,3′-piperidin]-2-one and acetaldehyde (5equivalents). Yield: 45 mg (26%). ¹³C NMR of the HCl-salt (CD₃OD): δ9.6,19.8, 31.3, 46.3, 54.2, 54.3, 55.1, 111.5, 123.9, 124.4, 130.4, 131.3,142.6, 182.3

Example 21 1′-Propyl-spiro[indoline-3,3′-piperidin]-2-one hydrochloride

[0439] The compound was prepared according to PROCEDURE 1, Method A byreaction with spiro[indoline-3,3′-piperidin]-2-one and propionaldehyde(5 equivalents). Yield 65%.

Example 22 1′-Isopropylspiro[indoline-3,3′-piperidin]-2-one

[0440] The compound was prepared according to PROCEDURE 1, Method A byreaction with spiro[indoline-3,3′-piperidin]-2-one and acetone (5equivalents). Yield: 75%. ¹³C NMR (CDCl₃): δ17.6, 17.7, 21.7, 32.1,48.6, 48.8, 54.0, 54.8, 109.6, 121.6, 126.2, 127.2, 134.8, 140.1, 182.4;MS (CI, CH₄): m/z (rel. int.) 245 (M+1, 100)

Example 23 1′-Allylspiro[indoline-3,3′-piperidin]-2-one

[0441] The compound was prepared according to PROCEDURE 1, Method B byreaction of spiro[indoline-3,3′-piperidin]-2-one with allyl bromide (1.1equivalents). ¹³C NMR (CDCl₃): δ21.2, 31.3, 48.4, 53.3, 58.1, 61.6,109.5, 117.2, 121.6, .125.7, 127.4, 134.3, 135.1, 140.0, 181.6; MS (CI,CH₄): m/z (rel. int.) 243 (M+1, 100)

Example 24 1′-Cyclopropylmethylspiro[indoline-3,3′-piperidin]-2-one

[0442] The compound was prepared according to PROCEDURE 1, Method A byreaction of spiro[indoline-3,3′-piperidin]-2-one with 3 equiv. ofcyclopropanecarboxaldehyde. Yield: 90%. ¹³C NMR (CDCl₃): δ3.8, 4.0, 8.3,21.4, 31.8, 48.6, 53.3, 58.4, 63.6, 109.7, 121.7, 126.1, 127.4, 134.7,140.0, 182.2; MS (CI, CH₄): m/z (rel. int.) 257 (M+1, 100)

Example 25 1′-Butylspiro[indoline-3,3′-piperidin]-2-one

[0443] The compound was prepared according to PROCEDURE 1, Method A byreaction with spiro[indoline-3,3′-piperidin]-2-one and butyraldehyde (10equiv.). ¹³C NMR (CDCl₃): δ14.1, 20.6, 21.7, 29.1, 32.0, 49.0, 53.8,58.5, 58.9, 109.9, 121.9, 126.4, 127.6, 134.9, 140.2, 182.4; MS (TSP):m/z (rel. int.) 260/259 (M⁺, 25/100)

Example 26 1′-s-Butylspiro[indoline-3,3′-piperidin]-2-one

[0444] The compound was prepared according to PROCEDURE 1, Method A byreaction with spiro[indoline-3,3′-piperidin]-2-one and 2-butanone (3equivalents). Yield: 46%. ¹³C NMR (CDCl₃): δ11.5, 11.6, 13.3, 13.3,21.7, 21.9, 26.4, 26.5, 32.1, 32.1, 46.1, 48.6, 49.0, 50.9, 52.4, 56.6,61.2, 62.5, 109.6, 121.5, 121.6, 126.4, 126.5, 127.2, 134.7, 134.9,140.1, 140.1, 182.4, 182.5; MS (CI, CH₄): m/z (rel. int.) 259 (M+1, 100)

Example 27 1′-Isobutylspiro[indoline-3,3′-piperidin]-2-one hydrochloride

[0445] The compound was prepared according to PROCEDURE 1, Method A byreaction with spiro[indoline-3,3′-piperidin]-2-one and isobutyraldehyde(3 equivalents). Purification on SiO₂ twice (eluent: DCM/MeOH). Yield:88 mg. ¹³C NMR (CD₃OD): δ21.2, 21.3, 22.7, 26.7, 32.9, 50.2, 55.4, 60.4,68.3, 110.6, 122.6, 127.4, 128.6, 136.0, 141.8, 183.0; MS (CI, CH₄): m/z(rel. int.) 259 (M+1, 100)

Example 28 1′-Cyclobutylspiro[indoline-3,3′-piperidin]-2-onehydrochloride.

[0446] The compound was prepared according to PROCEDURE 1, Method A byreaction with spiro[indoline-3,3′-piperidin]-2-one and cyclobutanone (5equivalents). ¹³C NMR of the HCl-salt (CD₃OD): δ14.4, 19.4, 26.1, 26.9,31.2, 46.1, 50.4, 53.9, 61.6, 111.5, 123.9, 124.6, 130.4, 131.3, 142.6,182.2; MS (CI, CH₄): m/z (rel. int.) 257 (M+1, 100).

Example 29 1′-Methoxyethylspiro[indoline-3,3′-piperidin]-2-onehydrochloride

[0447] The compound was prepared according to PROCEDURE 1, Method B byreaction with spiro[indoline-3,3′-piperidin]-2-one and 2-chloroethylmethylether (1.2 equivalents) and potassium iodide (catalytic amount).EtOAc was used for extraction. Yield: 74% ¹³C NMR (CDCl₃): δ21.8, 31.8,48.8, 54.2, 58.0, 58.8, 59.2, 70.8, 109.8, 122.0, 126.4, 127.6, 134.8,140.2, 182.0. The HCl salt was prepared. MS (TSP): m/z (rel. int.)262/261 (M⁺, 16/100).

Example 30 1′-Methylthioethylspiro[indoline-3,3′-piperidin]-2-onehydrochloride

[0448] The compound was prepared according to PROCEDURE 1, Method B byreaction with spiro[indoline-3,3′-piperidin]-2-one, 2-chloroethylmethylsulfide (1.2 equivalents) and potassium iodide (catalytic amount).¹³C NMR (CDCl₃): δ15.9, 21.7, 31.8, 31.9, 48.9, 53.3, 58.0, 58.8, 109.8,122.1, 126.6, 127.7, 134.6, 140.2, 181.9.

[0449] The HCl salt was prepared. MS (EI, 70 eV): m/z (rel. int.)278/277 (M⁺, 16/100).

Example 31 1′-Methoxypropylspiro[indoline-3,3′-piperidin]-2-onehydrochloride

[0450] The compound was prepared according to PROCEDURE 1, Method B byreaction with spiro[indoline-3,3′-piperidin]-2-one, 3-chloropropylmethyl ether (1.2 equivalents) and potassium iodide (catalytic amount).¹³C NMR (CDCl₃): δ21.8, 27.3, 32.0, 48.8, 53.8, 55.4, 58.8, 58.9, 71.1,109.6, 122.0, 126.6, 127.7, 134.8, 140.0, 181.4.

[0451] The HCl salt was prepared. MS (TSP): m/z (rel. int.) 276/275 (M⁺,15/100).

Example 32 (S)-1′-(3-Fluoropropyl)spiro[indoline-3,3′-piperidin]-2-onehydrochloride

[0452] The racemic compound was prepared according to PROCEDURE 1,Method B by reaction of spiro[indoline-3,3′-piperidin]-2-one with1-bromo-3-fluoropropane (1.0 equivalent). EtOAc was used for extraction.Yield: 69%. ¹³C NMR (CDCl₃): δ21.8, 28.0 (d, J_(F)=20 Hz), 31.8, 48.9,53.9, 54.3 (d, J_(F)=5 Hz), 58.7, 81.7, 83.3, 110.0, 122.0, 126.2,127.7, 134.7, 140.3, 182.1. The racemate was separated on the KirasilTBB column and the HCl salt was prepared.

Example 33 (S)-(+)-1′-Propylspiro[indoline-3,3′-piperidin]-2-one

[0453] 1′-Propyl-1H-spiro[indole-3,3′-piperidin]-2-one (2.9 g, 11.9mmol) and di-p-toluoyl-L-tartraric acid (4.6 g, 11.9 mmol) weredissolved in ethanol (50 ml) at 40-50° C. Water was added in smallportions (totally 50 ml) at the same temperature leaving a clearsolution which was slowly cooled to 5° C. The crystals (3.53 g) werecollected the next day. A second crystallisation was carried out in asimilar manner using the same volume of solvents yielding pure(S)-1′-propylspiro[indole-3,3′-piperidinium]-2-onedi-p-toluoyl-L-tartrate (3.2 g) which was converted to the correspondingamine by a treatment with an excess of aqueous sodium bicarbonate. Theamine was extracted into ethyl acetate, the extracts were dried oversodium sulfate and concentrated in vacuum. The residue was dissolved inacetonitrile and treated with a 1.5 fold molar excess of hydrochloricacid.

[0454] Removal of the volatiles in vacuum and coevaparation withacetonitrile yielded (S)-1′-propylspiro[indole-3,3′-piperidinium]-2 onehydrochloride (1.13 g, 78%), [α]_(D) ²⁰+91.9° (c 1.00, H₂O). Theabsolute configuration was established by X-ray crystallography of thedi-p-toluoyl-L-tartrate.

Example 34 (R)-(−)-1′-Propylspiro[indoline-3,3′-piperidin]-2-one

[0455] The mother liquid from the first crystallisation in the previousEXAMPLE, consisting mostly of the other diastereomeric salt was treatedwith NaHCO₃/ethyl acetate to leave the levorotatory amine. This wastreated with 1 mol. eq. of di-p-toluoyl-D-tartraric acid and the saltwas crystallised from 50% aqueous ethanol. A similar further treatmentas in EXAMPLE 27 yielded(R)-1′-propylspiro[indole-3,3′-piperidinium]-2-one hydrochloride (1.09g, 75%), [α]_(D) ²⁰ (c 1.00, H₂O).

Example 35 Spiro[indoline-3,3′-perhydroazepin]-2-one

[0456] STEP A. N-Benzyl-4-(3-indolyl)-butanamine. Lithium aluminumhydride (4.8 g) was added to a solution of N-benzyl-3-indolebutanamide(18.73 g) in dry THF (200 mL) at nitrogen atmosphere and at 0° C. Afterstirring at reflux for 15 h and work-up with sodium hydroxide the titlecompound was obtained as pale yellow crystals (16.4 g).

[0457] STEP B. 3-(4-(Benzylamino)-butyl)-indolin-2-one. Conchydrochloric acid (90 mL) was added to a solution of the compound fromthe previous step in DMSO (38 mL) and MeOH (8 mL). After stirring for 30min at 0° C. and 30 min at room temperature the mixture was poured ontoice followed by extractive work-up. The title compound was obtained as acrude orange oil (16.2 g).

[0458] STEP C. 1′-Benzylspiro[indoline-3,3′-perhydroazepin]-2-one. Asolution of the compound from the previous step (15.5 g) was cyclisedvia a Mannich reaction following the procedure described in J Med Chem1976, 19, 892. Evaporation, extractive work-up and purification onsilica gave the title compound as a yellow oil (2.4 g).

[0459] STEP D. Spiro[indoline-3,3′-perhydroazepin]-2-one hydrochloride.The compound from the previous step was hydrogenated in acetic acid over10% Pd/C at 40 psi H₂ for 48 h. Evaporation and extractive work-up gavethe title compound as a yellow solid (1.51 g). MS (TSP+) m/z: 217 (M+H⁺,100) which was converted to the title compound.

EXAMPLE 36 1′-Propylspiro[4-azaindoline-3,3′-piperidin]-2-one

[0460] STEP A. tert-Butyl3-[(2-bromo-3-pyridyl)carbamoyl]-1,2,5,6-tetrahydropyridine-1-carboxylate.2-Bromo-3-pyridineamine (3.0 g, 17.3 mmol) and1,2,5,6-tetrahydro-1,3-pyridinedicarboxylic acid 1-tert-butyl ester3-methyl ester (5.05 g, 20.8 mmol) were dissolved in DCM (80 ml). To thesolution trimethylaluminium (26 mmol, 2M solution) was slowly added at0° C. The mixture was refluxed overnight. Work-up and purification onsilica gel using 60% ethyl acetate in heptane as an eluent gave 5.65 g(85%) of the title compound.

[0461] STEP B. tert-Butyl3-[N-(2-bromo-3-pyridyl)-N-(tert-butoxycarbonyl)carbamoyl]-1,2,5,6-tetrahydropyridine-1-carboxylate.The compound from STEP A was dissolved in DCM anddi-tert-butyl-dicarbonate (3.85 g, 17.6 mmol) was added followed bytriethylamine (2.51 ml, 18.0 mmol) and dimethylaminopyridine (0.17 g,1.4 mmol). After stirring the mixture for 1 h at room temperaturemethanol was added and the volatiles were removed in vacuum.Purification of the product on a column packed with silica gel using 40%ethyl acetate in heptane as an eluent afforded 6.74 g, (95%) of thetitle compound.

[0462] STEP C. Di-t-butyl2-oxo-1,1′-spiro[4-azaindoline-3,3′-(1,2,3,6-tetrahydropyridin)]-1,1′-dicarboxylate.The compound from STEP B was dissolved in acetonitrile (80 ml),palladium acetate (0.37 g, 1.67 mmol) and triphenylphosphine (1.0 g, 3.8mmol) were added and finally triethylamine (2.9 ml, 20.8 mmol). Themixture was refluxed under nitrogen for 2.5 hours. Work-up gave thetitle compound (4.13 g, 74%).

[0463] STEP D. Di-t-butyl2-oxo-1,1′-spiro[4-azaindoline-3,3′-piperidin]-1,1′-dicarboxylate. Thecompound from STEP C was hydrogenated in methanol over 10% Pd/C at 50psi H₂ for 3 h. Purification on a column packed with silica gel using60% ethyl acetate in heptane as an eluent gave the title compound (82%).

[0464] STEP E. 1′-Propylspiro[4-azaindoline-3,3′-piperidin]-2-one. Thecompound from STEP D was deprotected using a mixture of 36% hydrochloricacid, methanol and dioxane (1:1:5 volume per cent) at room temperaturefor 10 h. The volatiles were removed and the crudespiro[4-aza-indole-3,3′-piperidin]-2-one was alkylated according toPROCEDURE 1, Method A. The product was purified on a column with silicagel using 10-20% methanol in ethyl acetate as an eluent to give thetitle compound (57%). ¹³C NMR, δ ppm: 12.9, 20.6, 22.0, 31.0, 49.0,55.2, 58.1, 62.0, 117.3, 123.4, 136.6, 143.6, 155.4, 181.7.

Example 37 1′-Butylspiro[4-azaindoline-3,3′-piperidin]-2-one

[0465] The title compound was synthesised according to the proceduredescribed in EXAMPLE 29 using butanal. ¹³C NMR, δ ppm: 15.1, 21.8, 22.0,29.6, 31.0, 49.0, 55.3, 58.2, 60.0, 117.2, 123.4, 136.6, 143.7, 155.4,181.7.

Example 38 1′-s-Butylspiro[4-aza-indoline-3,3′-piperidin]-2-one

[0466] Was synthesised according to EXAMPLE 30 using sec-butanal. ¹³CNMR, δ ppm: 21.6, 21.9, 22.0, 26.3, 30.9, 49.1, 55.8, 58.4, 67.8, 117.2,123.4, 136.5, 143.6, 155.4, 181.7.

Example 39 1′-Propyl-5-chlorospiro[7-aza-indoline-3,3′-piperidin]-2-one

[0467] STEP A. 3-Bromo-5-chloro-2-pyridineamine. To5-chloro-2-pyridineamine (3 g,23.3 mmol) dissolved in acetic acid (40ml) a solution of bromine (1.29 ml, 25 mmol) in acetic acid was addeddropwise at 10° C. The mixture was stirred for 2 h at room temperatureand then concentrated. Work-up and purification on a column packed withsilica gel using 40% ethyl acetate in heptane as an eluent yielded thetitle compound as a colourless powder (3.58 g, 74%).

[0468] STEP B. t-Butyl3-[N-(3-bromo-5-chloro-2-pyridyl)-N-(tert-butoxycarbonyl)carbamoyl]-1,2,5,6-tetrahydropyridine-1-carboxylate.The compound from STEP A was treated in a similar manner as wasdescribed in EXAMPLE 29, STEPS A and B affording the title compound ingood yield.

[0469] STEP C. Di-t-butyl5-chloro-2-oxo-1,1′-spiro[7-azaindoline-3,3′-piperidin]-1,1′-dicarboxylate.The previous amide was cyclized as described in EXAMPLE 29, STEP C andthe resulting product was hydrogenated in methanol under 50 psi H₂ over10% Pd/C for 20 hours to give the title compound after chromatograficseparation on silica gel. The dechlorinated compound was also obtainedin 40% yield.

[0470] STEP D. 5-Chloro-spiro[7-azaindoline-3,3′-piperidin]-2-one. Thecyclized product from the previous step was deprotected as described inEXAMPLE 29.

[0471] STEP E.1′-Propyl-5-chloro-spiro[7-azaindoline-3,3′-piperidin]-2-one. Thecompound from the previous step was converted to the title compound asdescribed in EXAMPLE 29. ¹³C NMR, δ ppm: 12.8, 21.0, 22.8, 32.3, 49.9,54.5, 59.3, 61.4, 118.6, 119.3, 135.2, 146.7, 156.7, 181.1.

Example 40 1′-Propylspiro[7-azaindoline-3,3′-piperidin]-2-one

[0472] The dechlorinated product from EXAMPLE 33, Step C, wasdeprotected and alkylated as described in the previous exampel. ¹³C NMR,δ ppm: 12.7, 20.8, 22.7, 32.2, 50.3, 54.1, 59.3, 61.4, 123.3, 127.0,135.8, 145.4, 154.3, 180.4.

Example 41 1′-Propyl-6-methylspiro[7-azaindoline-3,3′-piperidin]-2-one

[0473] STEP A. 2-Amino-6-methylpyrid-3-yl trifluoromethanesulfonate. Toa stirred suspension of 2-amino-6-methylpyridin-3-ol (2 g) in DCM (50ml) containing triethylamine (2.2 g), trifluoromethanesulfonic anhydride(5.3 g) was added under N₂ at −78° C. After the mixture becamehomogeneous, it was allowed to warm to −20° C. and then quenched withaqueous NaHCO₃. Work-up by extraction into chloroform purification onsilica gel using 40% ethyl acetate in heptane as an eluent afforded thetitle compound (86%).

[0474] STEP B.4-(6-Methyl-3-trifluoromethanesulfonyloxypyrid-2-ylcarbamoyl)-3,6-dihydro-2H-pyridine-1-carboxylicacid t-butyl ester. The compound from STEP A was treated in a similarmanner as was described in EXAMPLE 29, STEP A affording the titlecompound in 42% yield.

[0475] STEP C. t-Butyl6-methyl-2-oxo-spiro[7-azaindoline-3,3′-(1,2,3,6-tetrahydropyridin)]-1′-carboxylate.The compound from STEP B was treated in a similar manner as wasdescribed in EXAMPLE 29, STEP. C affording the title compound in 76%yield.

[0476] STEP D. t-Butyl6-methyl-2-oxo-spiro[7-azaindoline-3,3′-piperidin]-1′-carboxylate. Thecompound from STEP C was treated in a similar manner as was described inEXAMPLE 29, STEP D affording the title compound in 85% yield.

[0477] STEP E.6-Methyl-1′-propylspiro[7-azaindoline-3,3′-piperidin]-2-onedihydrochloride. The compound from STEP D was treated in a similarmanner as was described in EXAMPLE 29, STEP E affording the titlecompound in 66% yield. ¹³C NMR, δ ppm: 12.8, 21.0, 22.9, 24.2, 32.4,49.7, 54.7, 59.6, 61.4, 117.5, 127.0, 135.4, 156.4, 156.9, 181.5. It wasconverted to the dihydrochloride by treatment with HCl in ethanol andevaporation of solvents.

Example 42 1′-Propylspiro[isoindoline-3,3′-piperidin]-1-onehydrochloride

[0478] STEP A. 2-Bromo-N-(3-pyridyl)benzamide. To a solution of2-bromobenzoylchloride (11.6 g) in dry pyridine (50 ml) at rt.,3-aminopyridine (5.0 g) dissolved in dry pyridine was added. Afterstirring for 12 hours and extractive work-up 7.77 g of the title productwas obtained as white crystals. MS(ESP+) m/z: 279 (M+H+,98), 277 (M+H+,100).

[0479] STEP B.2-Bromo-N-(1-propyl-1,2,5,6-tetrahydropyridin-3-yl)benzamide. To astirred solution of the compound from Step A (6.0 g) in dry toluene (100ml) propylbromide (13.0 g) was added. The reaction mixture was stirredat 80° C. for 16 hours. The precipitated oil was dissolved in MeOH (100ml) and sodium borohydride (6.0 g) was added slowly at rt. After 3 hoursof reaction time, work-up and chromatography on silica gel with ethylacetate/n-heptane as the eluent 6.65 g of the title product was obtainedas an oil. MS(TSP+) m/z: 325 (M+H+, 92), 323 (M+H+, 100).

[0480] STEP C.2-Iodo-N-(1-benzyl-1,2,5,6-tetrahydropyridin-3-yl)benzamide. To astirred solution of 2-iodo-N-pyridin-3-ylbenzamide (8.32 g) in drytoluene (200 ml) was added benzyl bromide (5.1 g). The reaction mixturewas stirred at 100 ° C. for 16 hours. The solvent was decanted from theprecipitated crystals which were dissolved in MeOH (150 ml) and thetreated with sodium borohydride to give 7.9 g of the title compound aswhite-yellow crystals. MS(TSP+) m/z: 419 (M+H+, 100).

[0481] STEP D. 1′-Propylspiro[isoindoline-3,3′-piperidin]-1-onehydrochloride. The compound from STEB B (6.60 g) was cyclised accordingto the general Heck procedure described in EXAMPLE 1 to give an oilwhich was chromatographed on silica gel with ethyl acetate/n-heptane asthe eluent to give 830 mg1′-propylspiro-[isoindoline-3,3′-1,2,3,6-tetrahydropyridin]-1-one as anoil. This compound was hydrogenated as described in EXAMPLE 1 yieldingthe free base of the title compound as white crystals. The titlecompound was also prepared from cyclization of the STEP C compoundfollowed by hydrogenation-debenzylation plus propylation. ¹³C NMR(CDC13): δ 169.44, 150.10, 131.77, 131.58, 128.51, 124.14, 121.56,62.74, 60.87, 60.26, 53.24, 34.88, 23.34, 19.00, 11.82.; MS(TSP+) m/z:245 (M+H+, 100); MS(CI, NH3): 245 (M+H+, 100), 180 (3). Mp: 110-112°.

[0482] The title compound was prepared by treating it with HCl in Et2O.Anal. Calcd for C15H21ClN2O: C, 64.13; H, 7.53; N 10.01 Found: C, 64.25;H, 7.6; N, 10.0.

Example 43 Spiro[3,4-dihydro-1H-quinoline-3,3′-piperidin]-2-onehydrochloride

[0483] STEP A. 1-t-Butyl 3-ethyl3-(2-nitrobenzyl)-1,3-piperidinedicarboxylate. To a solution of ethyl1-t-butyloxycarbonyl-3-piperidinecarboxylate (1.5 g) in THF (10 ml) at−78° C. was added lithium hexamethyldisilazide (8.74 ml of a 1M solutionin THF). A solution of 2-nitrobenzyl bromide. (1.5 g) in THF (5 ml) wasadded dropwise at −78° C. and the reaction mixture was allowed to reachroom temperature. Work-up and chromatography on silica gel with ethylacetate/petroleum benzine 5:1 as eluent gave 1.3 g of the titlecompound.

[0484] STEP B. 1′-t-Butylspiro[3,4-dihydro-1H-quinoline-3,3′-piperidin]-2-one-1-carboxylate. To asolution of 1-t-butyl 3-ethyl3-(2-nitrobenzyl)-1,3piperidinedicarboxylate (1.2 g) in methanol (25 ml)10% Pd/C (0.3 g) was added and the mixture was hydrogenated at 30 psifor 2 h. The mixture was filtered and concentrated to yield 0.95 g ofthe title compound.

[0485] STEP C. Spiro[3,4-dihydro-1H-quinoline-3,3′-piperidin]-2-onehydrochloride. The compound (0.90 g) from STEP B was debocylated inethyl acetate HCl-diethyl ether and the deprotected amine wasprecipitated as the hydrochloride salt. ¹³C NMR (CD₃OD, 400 MHz): δ20.24, 29.95, 37.14, 38.83, 45.01, 50.28, 116.26, 122.08, 124.74,129.00, 129.83, 137.42, 175.17.

Example 44 1′-Propylspiro[3,4-dihydro-1H-quinoline-3,3′-piperidin]-2-one hydrochloride

[0486] Spiro[3,4-dihydro-(1H)-quinoline-3,3′-piperidin]-2-one (0.55 g)was propylated according to the general PROCEDURE 1, Method A. The crudeproduct was purified by flash chromatography on silica gel withDCM/methanol 9:1 as eluent to give 0.44 g of the title compound as thefree base. ¹³C NMR (CDCl₃, 400 MHz): δ 11.74, 19.85, 21.18, 29.12,33.28, 40.82, 54.47, 57.34, 60.51, 114.67, 122.90, 123.03, 127.17,128.59, 136.48, 175.64. The product was converted to the hydrochlorideby dissolving the base in di ethyl ether and precipitate with HCl inEt₂O.

Example 45

[0487] 1′-Isopropylspiro[indoline-3,3′-piperidine]hydrochloride. To asolution of 1′-isopropylspiro[indoline-3,3′-piperidin]-2-one (0.2 g) inTHF (10 ml) borane-dimethyl sulfide complex in THF (2 M solution, 0.90ml) was added. The reaction mixture was refluxed for 1 h. The solventwas evaporated in vacuo and the residue was refluxed with one equivalentof HCl (g) in ethanol for 30 minutes. After work-up the residue waspurified by flash chromatography on silica gel with ethyl acetate aseluent to yield 0.12 g of the base. 13C NMR (CDCl3, 400 MHz): δ 16.3,19.6, 23.7, 35.1, 46.2, 50.2, 54.9, 57.2, 57.3, 109.7, 118.2, 123.2,128.0, 135.9, 151.8. It was converted to the hydrochloride with HCl inether.

Example 461′-Methylspiro[2,3-dihydrobenzofuran-3,3′-piperidine]hydrochloride

[0488] STEP A. 2-Iodophenyl(1-methyl-1,2,5,6-tetrahydro-3-pyridinyl)methyl ether. To an ice-cooledstirred solution of triphenylphosphine (1.54 g) and diethylazodicarboxylate (0.92 ml) in THF (20 ml) 2-iodophenol (1.27 g) and(1-methyl-1,2,5,6-tetrahydro-3-pyridyl)methanol (0.5 g) were added. Themixture was stirred for 72 h at room temperature. The solvent wasevaporated and the residue was purified by chromatography on silica gelwith first ethyl acetate and then 10% methanol in DCM as eluent to yield0.98 g of the title compound.

[0489] STEP B.1′-Methylspiro[2,3-dihydrobenzofuran-3,3′-(1,2,3,6-tetrahydropyridin)].The prevoius compound (0.42 g) was cyclized following the procedure inEXAMPLE 1 using tri-o-tolylphosphine to yield 0.2 g of the titlecompound.

[0490] STEP C.1′-Methylspiro[2,3-dihydrobenzofuran-3,3′-piperidine]hydrochloride. To asolution of the previous compound (0.2 g) in acetic acid (10 ml) 10%Pd/C (0.1 g) was added and the mixture was hydrogenated in a Parrapparatus at 50 psi for 6 h. The residue after filtering and evaporationof solvents gave 0.2 g of the title compound. 13C NMR (CDCl3, 400 MHz):δ 22.9, 34.1, 46.1, 46.6, 55.5, 65.0, 81.0, 109.6, 120.1, 123.1, 128.5,133.9, 158.5. It was converted to the hydrochloride.

Example 471′-Propylspiro[2,3-dihydrobenzofuran-3,3′-piperidine]hydrochloride

[0491] STEP A.Spiro[2,3-dihydrobenzofuran-3,3′-(1,2,3,6-tetrahydropyridine)]. To astirred solution of the product from EXAMPLE (0.32 g) in1,2-dichloroethane (20 ml) 1-chloroethyl chloroformate (0.46 g) wasadded and the mixture was refluxed for 36 h. After concentrationmethanol (10 ml) was added and the mixture was refluxed for 4 h.Concentration gave 0.3 g of the product.

[0492] STEP B.1′-Propylspiro[2,3-dihydrobenzofuran-3,3′-(1,2,3,6-tetrahydropiperidine)].The previous compound was propylated according to PROCEDURE 1, METHOD Bgiving the title compound in 60% yield.

[0493] STEP C.1′-Propylspiro[2,3-dihydrobenzofuran-3,3′-piperidine]hydrochloride. Theprevious compound was hydrogenated at 50 psi for 6 h over Pd/C. Work-upyielded the title compound. 13C NMR (CDCl₃): δ 12.1, 20.2, 22.8, 34.8,46.2, 54.1, 60.5, 63.0, 81.8, 109.9, 120.3, 123.2, 128.6, 133.9, 159.5.It was converted to the hydrochloride.

Example 48 Spiro[3,4-dihydro-1H-quinoline-4,3′-piperidin]-2-onehydrochloride

[0494] STEP A. N-(2-Iodophenyl)-2-(4-pyridinyl)acetamide. A solution of3-pyridylacetic acid (2.0 g) and triethylamine (2.0 mL) in dry THF (20mL) was treated at −10° C. with isobutyl chloroformate (2.0 mL). After10 minutes at −10° C., a solution of 2-iodo-aniline (3.6 g) in THF (10mL) was added. The reaction mixture was allowed to stir while slowlywarming to room temperature. The solvent was evaporated, and the residuewas partitioned between ethyl acetate and saturated NaHCO₃ solution. Theorganic layer was dried over MgSO₄, filtered, the solvent was evaporatedand the residual oil was purified by flash chromatography to yield 1.0 gof the title product. MS (TSP+) m/z [M+H]⁺: 339.

[0495] STEP B.2-(1-Benzyl-1,2,3,6-tetrahydro-4-pyridinyl)-N-(2-iodophenyl)acetamide.Benzyl bromide (1.0 g) was added to a solution ofN-(2-iodophenyl)-2-(4-pyridinyl)acetamide (1.0 g) in acetone. Themixture was stirred at reflux over night. The resulting viscous oil wasdecanted and used without further purification. To a stirred solution ofthe pyridinium salt in methanol (20 mL) was added portionwise NaBH₄(0.14 g) at 0° C. during 1 hour. On completion of the addition, theresulting mixture was allowed to warm to room temperature and stirredovernight. Water was added carefully and the resulting mixture wasconcentrated in vacuo. The residue was extracted twice with ethylacetate. The organic layer was dried over MgSO₄, filtered, the solventwas evaporated and the residual oil was purified by flash chromatographyto yield 1.0 g of the title product. MS (TSP+) m/z [M+H]⁺: 433.

[0496] STEP C.1′-Benzylspiro[3,4-dihydro-1H-quinoline-4,3′-1,2,3,6-tetrahydropyridin]-2-one.The product from STEP B (0.7 g) was dissolved in acetonitrile (20 mL)and triethylamine (0.50 mL) under N₂-atmosphere. After 0.5 htri-o-tolylphosphine (90 mg) and palladium acetate (36 mg) were added inone portion. The mixture was refluxed for 18 hours under N₂-atmosphere.The crude product was purified by chromatography on silica gel andeluted with ethyl acetate to give the title compound (0.3 g) as a yellowoil. MS (TSP+) m/z [M+H]⁺: 305.

[0497] STEP D. Spiro[3,4-dihydro-1H-quinoline-4,3′-piperidin]-2-onehydrochloride. The product from STEP C was hydrogenated in glacialacetic acid (20 mL) using 10% Pd/C and H₂ (3.5 atm) for 18 hours. Thecatalyst was filtered off and the solution was concentrated in vacuo.The residue was dissolved in DCM and saturated NaHCO₃ solution and thewater layer was extracted three times with DCM. The organic layer wasdried over MgSO₄, filtered, the solvent was evaporated to yield 0.13 gof the title compound as the free base. ¹³C NMR (CDCl₃, 400 MHz): δ22.0,33.3, 36.2, 38.3, 46.5, 54.3, 116.1, 123.3, 124.9, 127.6, 130.5, 136.6,171.3. The product was converted to the hydrochloride by dissolving thebase in ethyl acetate and precipitate with HCl in Et₂O.

Example 49(S)-(−)-5-Methylspiro[7-azaindoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-onedihydrochloride

[0498] STEP A. t-Butyl3-(3-bromo-5-methyl-2-pyridylcarbamoyl)-1,2,5,6-tetrahydropyridine-1-carboxylate.It was prepared analogously to EXAMPLE 36, STEP A. in a yield of 53%.

[0499] STEP B. t-Butyl3-[N-(3-bromo-5-methyl-2-pyridyl)-N-(tert-butoxycarbonyl)carbamoyl]-1,2,5,6-tetrahydropyridine-1-carboxylate.The compound from STEP A was converted to the semisolid title compoundin a yield of 50% as described in EXAMPLE 36, STEP B.

[0500] STEP C. Di-t-butyl5-methyl-2-oxo-1,1′-spiro[7-azaindoline-3,3′-(1,2,3,6-tetrahydropyridin)]-1,1′-dicarboxylate.The compound from STEP B was treated as described in EXAMPLE 36, STEP Cto give the title compound in 80% yield.

[0501] STEP D. t-Butyl5-methyl-2-oxo-1,1′-spiro[7-azaindoline-3,3′-(1,2,3,6-tetrahydropyridin)]-1,1′-carboxylate.The compound from STEP C was treated in methanol at reflux with 10equivalents of ammonium acetate for 2 h. The residue after evaporationof solvent was purified by SGC (EtOAc:isohexanes 1:1 to pure EtOAc) togive the title compound as a white solid. Due to the presence ofrotamers it was difficult to obtain good NMR spectra.

[0502] STEP E. (S)-(+)-t-Butyl5-methyl-2-oxo-1,1′-spiro[7-azaindoline-3,3′-(1,2,3,6-tetrahydropyridin)]-1′-carboxylate.The compound from STEP D was chromatographically resolved on a KirasilTBB column using heptane/2-PrOH 9:1 as an eluent and recycling theeluate twice.

[0503] STEP F.(S)-(−)-5-Methylspiro[7-azaindoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-onedihydrochloride. The compound from STEP E, second peak, was deprotectedusing 0.5 M HCl in methanol-ether at room temperature for 15 h.Evaporation of solvents gave the title compound in quantitative yield.It is tentatively assigned the S configuration based on its elutionpattern on the chiral column. MS (TSP+) m/z [M+H]+: 216.

[0504] [α]₅₈₉ ²² −36° (c 1.0, MeOH).

Example 50(R)-(+)-5-Methylspiro[7-azaindoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-onedihydrochloride

[0505] The material from STEP E, first peak, was deprotected similarly.13C-NMR (d4-MeOH): 177.6, 152.5, 143.0, 135.6, 131.7, 129.8, 127.4,123.7, 47.7, 45.6, 42.2, 17.9 ppm. [α]₅₈₉ ²²+39° (c 1.04, MeOH).

Example 51(S)-5,6-Dimethylspiro[7-azaindoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-onehydrochloride

[0506] STEP A. t-Butyl3-(3-bromo-5,6-dimethyl-2-pyridylcarbamoyl)-1,2,5,6-tetrahydropyridine-1-carboxylate.It was prepared analogously to EXAMPLE 36, STEP A starting from3-bromo-5,6-dimethyl-2-pyridineamine (J. Heterocycl. Chem. 1994, 31,1641-5) in a yield of 57% after SGC (EtOAc: heptane 1:1→4:1). MS (TSP+)m/z [M+1]⁺: 410 and 412.

[0507] STEP B. t-Butyl3-[N-(3-bromo-5,6-dimethyl-2-pyridyl)-N-(tert-butoxycarbonyl)carbamoyl]-1,2,5,6-tetrahydropyridine-1-carboxylate.The compound from STEP A was converted to the crude title compound in ayield of 100% as described in EXAMPLE 36, STEP B. MS (TSP+) m/z[M−Boc+1]⁺410 and 412.

[0508] STEP C. Di-t-butyl5,6-dimethyl-2-oxo-1,1′-spiro[7-azaindoline-3,3′-(1,2,3,6tetrahydropyridin)]-1,1′-dicarboxylate.The compound from STEP B was treated as described in EXAMPLE 36, STEP Cto give the title compound in 70% yield.

[0509] STEP D. t-Butyl5,6-dimethyl-2-oxo-1,1′-spiro[7-azaindoline-3,3′-(1,2,3,6-tetrahydropyridin)]-1′-carboxylate.The compound from STEP C was treated in methanol at reflux with 10equivalents of ammonium acetate for 2 h. The residue after evaporationof solvent was purified by SGC (EtOAc:heptane 1:1) to give the titlecompound as a white solid. Due to the presence of rotamers it wasdifficult to obtain good NMR spectra. MS (TSP+) m/z [M+1]⁺330.

[0510] STEP E. (S)-t-Butyl5,6-dimethyl-2-oxo-1,1′-spiro[7-azaindoline-3,3′-(1,2,3,6-tetrahydropyridin)]-1′-carboxylate.The compound from STEP D was chromatographically resolved on a KirasilTBB column using heptane/2-PrOH 95:5 as an eluent and recycling theeluate twice.

[0511] STEP F.(S)-5,6-Dimethylspiro[7-azaindoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-onedihydrochloride. The compound from STEP E, second peak (190 mg), wasdeprotected using 0.5 M HCl in methanol-ether at room temperature for 15h. Evaporation of solvents gave the title compound in quantitativeyield. It is tentatively assigned the S configuration based on itselution pattern on the chiral column. MS (TSP+) m/z [M+H]⁺: 230. ¹H-NMR(d₄-MeOH): 7.80 (s, 1H), 6.11 (d, 1H), 5.54 (d, 1H), 3.75 (m, 2H), 3.52(dd, 2H), 2.42 (s, 3H), 218 (s, 2H).

[0512] The following EXAMPLES 52-81 were prepared analogously to EXAMPLE49 and 51 starting with an aniline or other aromatic amine. The mono-Bocprotected intermediates were separated using a Kirasil TBB (PROCEDURE 2)or Chiralpak AD column. All resolved compounds obtained from the lasteluting peak on the Kirasil TBB column are assumed to have the Sconfiguration, and vice versa.

Example 52(S)-5-Chlorospiro[7-azaindoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-onedihydrochloride

[0513]¹³C-NMR (D₂O), δ: 42.1, 45.5, 48.0, 123.7, 126.2, 126.7, 127.7,135.2, 146.4, 154.9, 180.0 ppm.

Example 53(R)-5-Chlorospiro[7-azaindoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-onedihydrochloride

[0514] MS (TSP+) m/z [M+H]⁺: 235

Example 54(R)-6-Methylspiro[7-azaindoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-onedihydrochloride

[0515]¹³C-NMR (D₂O): δ20.3, 42.0, 45.2, 47.3, 120.5, 123.1, 124.7,127.3, 140.2, 151.7, 153.4, 179.3 ppm.

Example 55(S)-6-Methylspiro[7-azaindoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-onedihydrochloride.

[0516] MS (TSP+) m/z [M+H]⁺: 216

Example 56(S)-7-Fluorospiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-onehydrochloride

[0517]¹³C-NMR (d₄-MeOH): 179.7, 149.9, 147.5, 133.3, 131.0, 130.4,126.3, 125.9, 125.1, 125.0, 121.16, 121.13, 117.9, 117.7, 109.5, 47.0,42.6, 30.7 ppm.

Example 57(R)-7-Fluorospiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-onehydrochloride

[0518] MS (TSP+) m/z [M+H]⁺: 219

Example 58(S)-4-Methylspiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-onehydrochloride

[0519]¹³C-NMR (d₄-MeOH): 180.1, 143.4, 137.0, 131.0, 127.1, 126.4,126.3, 125.2, 109.5, 45.6, 42.8, 17.8 ppm.

Example 59(R)-4-Methylspiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-onehydrochloride

[0520] MS (TSP+) m/z [M+H]⁺: 215

Example 60 (S)-Spiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-onehydrochloride

[0521] MS (TSP+) m/z [M+H]⁺: 201. ¹³C-NMR (d₄-MeOH): δ180.0, 141.6,131.1, 127.1, 125.5, 125.4, 124.3, 117.2, 47.2, 43.0 ppm.

Example 61 (R)-Spiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-onehydrochloride

[0522] MS (TSP+) m/z [M+H]⁺: 201

Example 62(R)-5,7-Difluorospiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-onehydrochloride

[0523] MS (TSP+) m/z [M+H]⁺: 237.

Example 63 (S)-5,7-Difluorospiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-one hydrochloride

[0524] MS (TSP+) miz [M+H]⁺: 237

Example 64(R)-5-Trifluoromethoxyspiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-onehydrochloride

[0525]¹³C-NMR (d₄-MeOH): 179.9, 146.1, 142.4, 132.1, 126.0, 125.9,124.3, 123.2, 120.7, 119.6, 112.6, 111.8, 46.6, 42.6, 30.7 ppm.

Example 65(S)-5-Trifluoromethoxyspiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-onehydrochloride

[0526] MS (TSP+) m/z [M+H]⁺: 285

Example 66(R)-5-Chlorospiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-onehydrochloride

[0527] MS (TSP+) m/z [M+H]⁺: 235. ¹H-NMR (d₄-MeOH): 7.4 (m, 1H), 7.37(d, 1H), 6.97 (d, 1H), 6.22 (d, 1H), 5.65 (d, 1H), 3.90 (m, 1H), 3.60(m,1H).

Example 67(S)-5-Chlorospiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-onehydrochloride

[0528] MS (TSP+) m/z [M+H]⁺: 235

Example 68(R)-5-Chloro-7-fluorospiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-onehydrochloride

[0529] MS (TSP+) m/z [M+H]⁺: 253. ¹H-NMR (d₄-MeOH): 7.3 (m, 2H), 6.2 (m,1H), 5.7 (m, 1H), 3.9 (m, 1H), 3.6 (m,1H). Enantiomeric purity 98.0%.

Example 69(S)-5-Chloro-7-fluorospiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-onehydrochloride

[0530] MS (TSP+) m/z [M+H]⁺: 253.

Example 70(R)-7-Chlorospiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-onehydrochloride

[0531] MS (TSP+) m/z [M+H]⁺: 235. ¹³C-NMR (d₄-MeOH): 180.0, 141.6,132.5, 131.4, 126.7, 126.1, 125.6, 124.3, 117.2, 47.2, 43.0 ppm.

Example 71(S)-7-Chlorospiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-onehydrochloride

[0532] MS (TSP+) m/z [M+H]⁺: 235.

Example 72(S)-6-Chlorospiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-onehydrochloride

[0533] MS (TSP+) m/z [M+H]⁺: 235. ¹³C-NMR (d₄-MeOH): 180.4, 145.1,137.0, 129.4, 127.0, 126.8, 126.0, 124.4, 112.6, 47.1, 43.0 ppm.

Example 73(S)-5-Methylspiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-onehydrochloride

[0534]¹³C-NMR (CDCl₃) δ180.2, 140.6, 134.1, 131.2, 130.4, 127.0, 125.9,125.2, 111.5, 48.0, 47.1, 42.7, 21.1. MS(ESP+) m/z calcd for [M−Cl]³⁰ :215, observed: 215.

Example 74(S)-5-Fluorospiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-onehydrochloride

[0535] MS (TSP+) m/z [M+H]⁺: 219. ¹H-NMR (d₄-MeOH): 7.1, 7.0, and 6.9 (3m, 3H), 6.18 (d, 1H), 5.57 (d, 1H), 3.85 (dd, 2H), 3.52 (s, 2H).

Example 75(S)-4-Chlorospiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-onehydrochloride

[0536] MS (TSP+) m/z [M+H]⁺: 235.

Example 76(R)-4-Methoxyspiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-onehydrochloride

[0537] MS (TSP+) m/z [M+H]⁺: 231. ¹³C-NMR (CDCl₃) δ179.7, 157.7, 144.2,132.6, 126.5, 124.5, 115.8, 107.2, 105.1, 56.3, 48.1, 45.8, 42.7.

Example 77(R)-6-Methoxyspiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-onehydrochloride

[0538] MS (TSP+) m/z [M+H]⁺: 231.

Example 78(S)-7-Fluoro-5-methylspiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-onehydrochloride

[0539] MS (TSP+) m/z [M+H]⁺: 233.

Example 795-Fluorospiro[7-azaindoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-onehydrochloride

[0540] MS (TSP+) m/z [M+H]⁺: 220.

Example 80(S)-6-Fluorospiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-onehydrochloride

[0541] MS (TSP+) m/z [M+H]⁺: 219. ¹H NMR (CD₃OD): δ7.1 (m, 1H), 6.6 (m,2H), 6.0 (d, 1H), 5.5 (d, 1H), 3.7 (s, 2H), 3.1 (s, 1H), 1.1 (s, 1H).

Example 81(S)-5-Methoxyspiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-onehydrochloride

[0542] MS (TSP+) m/z [M+H]⁺: 231. ¹H NMR (CDCl₃, 400 MHz) δ6.9 (d, 1H),6.8 (dd, 1H), 6.7 (d, 1H), 6.1 (d, 1H), 5.6 (d, 1H), 3.9 (s, 2NH), 3.8(s, 2H), 3.5 (d, 1H), 3.4 (d, 1H), 3.1 (s, 3H).

Example 826H-4,5-Dihydro-2-methylspiro[pyrrolo[2,3-c]pyrazole-4,3′-(1,2,3,6-tetrahydropyridin)]-5-onehydrochloride

[0543] The compound is made from commercially available3-amino-4-bromo-1-methylpyrazole following the general procedure viaHeck cyclisation described in Example 49.

Example 836H-4,5-Dihydro-2-methylspiro[thieno[2,3-b]pyrrole-4,3′-(1,2,3,6-tetrahydropyridin)]-5-onehydrochloride

[0544] The compound is made from known N-Boc-2-amino-4-iodothiophenefollowing the general procedure via Heck cyclisation described inExample 49.

Example 84 5-Chlorospiro[indoline-3,3′-piperidin]-2-one hydrochloride

[0545] The compound from EXAMPLE 65 was hydrogenated over Pd/C at 3 barin ethanol. MS (TSP+) m/z [M+H⁺: 237.

Example 85 Spiro[indoline-3,3′-(1,3,4,7-tetrahydro-2H-azepin)]-2-onehydrochloride

[0546] STEP A. 3-Allyl-3-[allyl(methyl)aminomethyl]-indolin-2-one.Oxindole was acylated with ethyl acetate in the presence of sodiumethoxide as described (Chem. Abstr. 1953, 47, p7488). The crude product(9.16 g; 52.3 mmol) was treated with sodium hydride (56 mmol) in DMF atice bath temperature for 30 min. Allyl bromide (51 mmol) was added andthe reaction mixture left at room temperature overnight. The crudeproduct after workup was purified by SGC (EtOAc/isohexanes 1:2). Theacetyl group was removed by treatment with triethylamine/water 1:1 at65° C. for 12 h and the the 3-allyloxindole thus obtained was treatedwith an excess of allylmethylamine and one equivalent ofparaformaldehyde in acetic acid at 70 for 4 h. The crude material afterevaporation of solvents was partioned between DCM and basic water. SGCusing EtOAc/isohexanes 1:1 gave a reddish oil of the title product(83%).

[0547] STEP B.N′-Methylspiro[indoline-3,3′-(1,3,4,7-tetrahydro-2H-azepin)]-2-one. Theproduct from the previous step (258 mg; 1.0 mmol) was treated withbis(tricyclopentylphosphine)benzylidene-Ru(IV) dichloride (104 mg; 0.14mmol) in dry toluene under nitrogen at 60° C. for three days. Anadditional 60 mg of the Ru-catalyst was added and the heating continuedovernight. SGC after evaporation of solvents yielded 55 mg (21%) of thetitle compound.

[0548] STEP C. t-Butyl2-oxospiro[indoline-3,3′-(1,3,4,7-tetrahydro-2H-azepine)]-1′-carboxylate.The spiro compound from STEP B (180 mg) was demethylated by treatmentwith 1-chloroethyl chloroformate in 1,2-dichloroethane at reflux for 2 hfollowed after evaporation of excess formiate by heating inmethanol-THF-water for 1 h. The secondary amine was bocylated bytreatment with (Boc)₂O and the product was chromatographed on theKirasil TBB column using heptane/iPrOH 9:1 as the eluent; two peaks werecollected.

[0549] STEP D.(S)-Spiro[indoline-3,3′-(1,3,4,7-tetrahydro-2H-azepin)]-2-onehydrochloride. The material from the second peak from STEP C (47 mg) wasdissolved in methanol (5 ml) and treated with HCl in ether (1.5 ml) atroom temperature overnight. The title compound was obtained upon removalof solvents. MS (TSP+) m/z [M+H]⁺: 215. ¹³C NMR: (CD3OD): 181.0, 142.1,132.7, 132.2, 130.4, 125.7, 124.8, 123.8, 111.6, 53.8, 47.6, 47.5, 35.4ppm.

Procedure 1 Exemplified General Methods for Synthesis of Tertiary Aminesby Alkylation of a Secondary Amine Method A

[0550] To a stirred solution of spiro[indoline-3,3′-piperidin]-2-one anda corresponding aldehyde or ketone (in excess) in methanol,sodiumcyanoborohydride (about 2 eq) was added. The pH was adjusted toabout pH 4-6 with acetic acid and the solution was stirred at room tempfor about 18-60 h. Concentration and extraction (EtOAc/1-2 M NH₃),drying of the combined organic phases and evaporation gave a crudeproduct. Purification by flash column chromatography (SiO₂, eluent:toluene/acetonitrile/triethylamine or acetone/isohexane) gave the titlecompound.

Method B

[0551] To a stirred solution of a spiro[indoline-3,3′-piperidin]-2-onein acetonitrile or DMF potassium carbonate (1.0-1.4 equivalents) and acorresponding alkyl halide (1.1-1.5 equivalents) was added at 0° C. orroom temp. The reaction mixture was stirred at room temp—60° C. for 2-15h. Concentration and extraction (DCM/water), drying of the combinedorganic phases and evaporation gave a crude product. Purification byflash column chromatography (SiO₂, eluent: acetone/isohexane ortoluene/acetonitrile/triethylamine) gave the title compound.

Procedure 2 Examples of Resolving Racemates by Chiral HPLC

[0552] The resolution of1′-isopropylmethylspiro[indoline-3,3′-piperidin]-2-one (861 mg) wasperformed by chiral HPLC on a Kirasil TBB (50×250 mm) column. Eluent:heptane/1-PrOH/1-BuOH 97:2:1. About 170 mg was loaded on the column eachtime and the substance was recycled twice on the column; 370 mg of(R)-enantiomer (>99% ee) and 380 mg of the (S)-enantiomer (93% ee) wereisolated.

[0553] Other tertiary amines could be similarly separated. In most casesit proved possible to check the enantiomeric purity of tertiary as wellas secondary amines using chiral liquid chromatography on for example aChiracel OD column.

[0554] It also proved possible to separate several mono-Boc derivativesof secondary amine intermediates on the Kirasil TBB column. One exampleis described in EXAMPLE 49, STEP E.

Biological Tests

[0555] 1. In Vivo Experiments

[0556] The compounds of the invention when given by systemic injectionto mice or rats, specifically reduce pain behavior in the formalin test.This test is an accepted model of clinical pain in man, involvingelements of nociceptor activation, inflammation, peripheralsensitization and central sensitization (A Tjølsen et al. Pain 1992, 51,5). It can therefore be inferred that the compounds can be used astherapeutic agents to relieve pain of various origins. The compounds ofthe table “Further most preferred compounds of the invention” exhibit ED50 doses by subcutaneous administration to mice in the range 0.2-6μmol/kg. The compounds of formula I also show analgesic activity in theintraarticular FCA (Freund's complete adjuvant) test in the rat, a modelof inflammatory pain (Iadarola et al. Brain Research 1988, 455, 205-12)and in the Chung nerve lesion test in the rat, a model for neuropathicpain (Kim and Chung. Pain 1992, 50, 355). The analgesic effects in theanimal models are obtained after doses that do not produce tissueconcentrations leading to conduction block in nerve fibers. Thus, theanalgesic effects can not be explained by the local anestheticproperties of the compounds mentioned in the publication by Kornet andThio. Analgesic efficacy after systemic administration is not a generalproperty of drugs with local anesthetic effects (Scott et al. BritishJournal of Anaesthesia 1988, 61, 165-8).

1. A compound of the formula I

in racemic form or in the form of an enantiomer, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is a) H, b) substituted orunsubstituted C₁-C₆ alkyl, c) C₁-C₆ alkoxy C₂-C₆ alkyl, d) C₁-C₆alkylthio C₂-C₆ alkyl, e) halogenated C₁-C₆ alkyl, f) aryl C₁-C₆ alkyl,g) C₁-C₆ alkenyl, or h) C₁-C₆ cycloalkyl C₁-C₂ alkyl; R² is a) H, b)C₁-C₆ alkyl, c) C₂-C₄ alkynyl, d) halogen, e) substituted orunsubstituted carbamoyl, f) substituted or unsubstituted carbamoyloxy,g) C₁-C₆ alkylcarbonyl, h) C₁-C₆ alkoxycarbonyl, i) C₁-C₆alkylcarbonyloxy, j) hydroxy-substituted C₁-C₆ alkyl, k) cyano, l)nitro, m) amino, n) halogenated C₁-C₆ alkyl, o) halogenated C₁-C₆alkoxy, p) halogenated C₁-C₆ alkylthio, q) C₁-C₆ alkylsulfinyl, r) C₁-C₆alkylsulfonyl, s) C₁-C₄ alkylsulfinylalkyl, t) C₁-C₄ alkylsulfonylalkyl,u) C₁-C₆ alkylsulfonylamino, v) halogenated C₁-C₆ alkylsulfonylamino, w)halogenated C₁-C₂ alkylsulfonyloxy, x) aminosulfonyl, y)aminosulfonyloxy, z) aryl, aa) heteroaryl, bb) arylcarbonyl, cc)heteroarylcarbonyl, dd) arylsulfinyl, ee) heteroarylsulfinyl, ff)arylsulfonyl, gg) heteroarylsulfonyl, in which any aromatic moiety isoptionally substituted, hh) C₁-C₆ alkylcarbonylamino, ii) C₁-C₆alkoxycarbonylamino, jj) C₁-C₆ alkyl-thiocarbonyl, kk) C₁-C₆alkoxy-thiocarbonyl, ll) formyl, or mm)alkoxysulfonylamino; R³ is a) H,b) C₁-C₆ alkyl, c) halogen, d) C₁-C₆ alkoxy, e) halogenated C₁-C₄ alkyl,f) halogenated C₁-C₆ alkoxy, g) halogenated C₁-C₆ alkylthio, h) C₁-C₄alkylsulfinyl, i) C₁-C₄ alkylsulfonyl, j) C₁-C₄ alkylsulfinyl C₁-C₆alkyl, k) C₁-C₄ alkylsulfonyl C₁-C₆ alkyl, l) C₁-C₄ alkylsulfonylamino,m)halogenated C₁-C₄ alkylsulfonylamino, n) aminosulfonyl, or o)aminosulfonyloxy; R⁴ is a) H, b) C₁-C₄ alkyl, or c) halogen; R² and R³may together with the carbon atoms to which they are attached, form asaturated or unsaturated ring, optionally containing one or more furtherheteroatoms, and/or optionally substituted with one or more substituentsselected from halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, CF₃, OH, cyano, amino,C₁-C₆ alkyl-NH—, (C₁-C₆ alkyl)₂—N—, CN, NH₂SO₂, NH₂CO—, or C₁-C₆alkyl-CO—; Any amino moiety in R²-R⁴ can obtionally be substituted withone or two C₁-C₆ alkyl groups which may be part of a ring; Ar is a)benzene, b) pyridine, c) thiophene, d) pyrazine, e) pyrimidine, f)oxazole, g) thiazole, h) pyrrole, i) pyrazole, or j) furan; X is a)—NHCO—, b) —CONH—, c) —NH—SO₂—, d) —SO₂NH—, e) —OCH₂—, f) —NHCH₂—, or g)—NHCOCH₂—; Y is a) —CH₂—, b) —CH(C₁-C₆ alkyl)-, c) —C(C₁-C₆ alkyl)₂-, ord) a single bond; Z is a) —CH₂CH₂CH₂—, b) —CH₂CH₂CH₂CH₂—, c) —CH═CHCH₂—,d) —CH═CHCH₂CH₂—, or e) —CH₂CH═CHCH₂—; provided that when X is —NHCOCH₂—then Y cannot be —CH₂—; and excluding the racemic compounds wherein Aris benzene, R²-R⁴ is hydrogen, X is NHCO, Y is a single bond, Z is—CH₂CH₂CH₂—, and R¹ is ethyl or n-propyl.
 2. A compound according toclaim 1, wherein R¹ is a) H, b) C₁-C₄ alkyl, c) C₁-C₄ alkoxy C₁-C₄alkyl, d) C₁-C₄ alkylthio C₁-C₄ alkyl, e) fluorinated C₁-C₄ alkyl, f)aryl C₁-C₄ alkyl, g) C₁-C₄ alkenyl, or h) cyclopropylmethyl; R² is a) H,b) C₁-C₄ alkyl, c) C₂-C₃ alkynyl, d) halogen, e) substituted orunsubstituted carbamoyl, f) substituted or unsubstituted carbamoyloxy,g) C₁-C₃ alkylcarbonyl, h) C₁-C₃ alkoxycarbonyl, i) C₁-C₃alkylcarbonyloxy, j) hydroxy-substituted C₁-C₃ alkyl, k) cyano, l)fluorinated C₁-C₃ alkoxy, m) fluorinated C₁-C₆ alkylthio, n) C₁-C₃alkylsulfinyl, o) C₁-C₃ alkylsulfonyl, p) C₁-C₃ alkylsulfinyl C₁-C₆alkyl, q) C₁-C₄ alkylsulfonyl C₁-C₆ alkyl, r) C₁-C₃ alkylsulfonylamino,s) halogenated C₁-C₃ alkylsulfonylamino, t) sulfamoyl, u) sulfamoyloxy,v) aryl, w) heteroaryl, x) heteroarylsulfinyl, y) arylsulfonyl, z)heteroarylsulfonyl, in which any aromatic moiety is optionallysubstituted, aa) C₁-C₄ alkylcarbonylamino, bb) C₁-C₃alkoxycarbonylamino, cc) C₁-C₃ alkyl-thiocarbonyl, or dd) C₁-C₃alkoxy-thiocarbonyl; R³ is a) H, b) C₁-C₄ alkyl, or c) halogen; R⁴ is a)H, b) C₁-C₄ alkyl, or c) halogen, R² and R³ may together with the carbonatoms to which they are attached, form a saturated or unsaturated ring,optionally containing one or more further heteroatoms, and/or optionallysubstituted with one or more substituents selected from halogen, C₁-C₆alkyl, C₁-C₆ alkoxy, CF₃, OH, cyano, amino, C₁-C₆ alkyl-NH—, (C₁-C₆alkyl)₂-N—, CN, NH₂SO₂, NH₂CO—, or C₁-C₆ alkyl-CO—; Any amino moiety inR²-R⁴ can obtionally be substituted with one or two C₁-C₆ alkyl groupswhich may be part of a ring; Ar is a) benzene, b) pyridine, c)thiophene, d) pyrazine, e) pyrimidine, f) oxazole, g) thiazole, h)pyrrole, i) pyrazole, or j) furan; X is a) —NHCO—, b) —CONH—, c)—NH—SO₂—, or d) —SO₂NH—; Y is a) —CH₂—, b) —CH(C₁-C₆ alkyl)—, c)—C(C₁-C₆ alkyl)₂—, or d) a single bond; Z is f) —CH₂CH₂CH₂—, g)—CH₂CH₂CH₂CH₂—, h) —CH═CHCH₂—, i) —CH═CHCH₂CH₂—, or j) —CH₂CH═CHCH₂—;provided that when X is —NHCOCH₂— then Y cannot be —CH₂—; and excludingthe racemic compounds wherein Ar is benzene, R²-R⁴ is hydrogen, X isNHCO, Y is a single bond, Z is —CH₂CH₂CH₂−, and R¹ is ethyl or n-propyl.3. A compound according to claims 1 to 2, wherein R¹ is a) H, b) C₁-C₄alkyl, or c) C₁-C₄ alkoxy C₁-C₄ alkyl; R² is a) H, b) C₁-C₄ alkyl, c)halogen, d) substituted or unsubstituted carbamoyl, e) substituted orunsubstituted carbamoyloxy, f) C₁-C₂ alkylcarbonyl, g) C₁-C₃alkoxycarbonyl, h) cyano, i) fluorinated C₁-C₂ alkoxy, j) fluorinatedC₁-C₆ alkylthio, k) C₁-C₃ alkylsulfinyl, l) C₁-C₃ alkylsulfonyl, m)C₁-C₂ alkylsulfonylamino, n) C₁-C₃ alkylcarbonylamino, or o) C₁-C₃alkoxycarbonylamino; R³ is a) H, b) C₁-C₄ alkyl, or c) halogen; R⁴ is a)H, b) C₁-C₄ alkyl, or c) halogen; R² and R³ may together with the carbonatoms to which they are attached, form a saturated or unsaturated ring,optionally containing one or more further heteroatoms, and/or optionallysubstituted with one or more substituents selected from halogen, C₁-C₆alkyl, C₁-C₆ alkoxy, CF₃, OH, cyano, amino, C₁-C₆ alkyl-NH—, (C₁-C₆alkyl)₂-N—, CN, NH₂SO₂, NH₂CO—, or C₁-C₆ alkyl-CO—; Any amino moiety inR²-R⁴ can obtionally be substituted with one or two C₁-C₆ alkyl groupswhich may be part of a ring; Ar is a) benzene, b) pyridine, c)thiophene, d) pyrazine, e) pyrimidine, f) oxazole, g) thiazole, h)pyrrole, i) pyrazole, or j) furan; X is a) —NHCO—, b) —CONH—, c)—NH—SO₂—, or d) —SO₂NH—; Y is a) —CH₂—, b) —CH(C₁-C₆ alkyl)—, c)—C(C₁-C₆ alkyl)₂—, or d) a single bond; Z is a) —CH₂CH₂CH₂—, b)—CH₂CH₂CH₂CH₂—, c) —CH═CHCH₂—, d) —CH═CHCH₂CH₂—, or e) —CH₂CH═CHCH₂—;excluding the racemic compounds wherein Ar is benzene, R²-R⁴ ishydrogen, X is NHCO, Y is a single bond, Z is —CH₂CH₂CH₂—, and R¹ isethyl or n-propyl.
 4. A compound according to claims 1 to 3, wherein R¹is H; R² is a) H, b) C₁-C₄ alkyl, or c) halogen; R³ is a) H, b) C₁-C₄alkyl, or c) halogen; R⁴ is d) H, e) C₁-C₄ alkyl, or f) halogen; Ar isa) benzene, or b) pyridine; X is a) —NHCO—, b) —CONH—, or c) —NH—SO₂—; Yis a single bond; Z is a) CH₂CH₂CH₂—, or b) —CH═CHCH₂—; excluding theracemic compounds wherein Ar is benzene, R²-R⁴ is hydrogen, X is NHCO, Yis a single bond, Z is —CH₂CH₂CH₂—, and R¹ is ethyl or n-propyl.
 5. Acompound or a pharmaceutically acceptable salt thereof, according toclaims 1 to 4 being 5-Fluorospiro[indolin-3,3′-piperidin]-2-one;5-Fluoro-1′-isopropylspiro[indolin-3,3′-piperidin]-2-one;(R)-5-Fluoro-1′-isopropylspiro[indolin-3,3′-piperidin]-2-one;(S)-5-Fluoro-1′-isopropylspiro[indolin-3,3′-piperidin]-2-one;5,7-Difluorospiro[indolin-3,3′-piperidin]-2-one acetate;5,7-Difluoro-1′-isopropylspiro[indolin-3,3′-piperidin]-2-one;(S)-5,7-Difluoro-1′-isopropylspiro[indolin-3,3′-piperidin]-2-one;1′,5-Dimethylspiro[indolin-3,3′-piperidin]-2-one;5-Methyl-1′-isopropyl-spiro[indolin-3,3′-piperidin]-2-one;6-Methyl-1′-isopropyl-spiro[indolin-3,3′-piperidin]-2-one;4-Methylspiro[indolin-3,3′-piperidin]-2-one;4-Methyl-1′-isopropylspiro[indolin-3,3′-piperidin]-2-one;4-Methyl-1′-propylspiro[indolin-3,3′-piperidin]-2-one;7-Fluorospiro[indolin-3,3′-(1,2,3,6-tetrahydropyridin)]-2-one;(S)-(+)-7-Fluorospiro[indolin-3,3′-piperidin]-2-one;Spiro[indolin-3,3′-piperidin]-2-one;1′-Ethylspiro[indolin-3,3′-piperidin]-2-one;1′-Propyl-spiro[indolin-3,3′-piperidin]-2-one;1′-Isopropylspiro[indolin-3,3′-piperidin]-2-one;1′-Allylspiro[indolin-3,3′-piperidin]-2-one;1′-Cyclopropylmethylspiro[indolin-3,3′-piperidin]-2-one;1′-Butylspiro[indolin-3,3′-piperidin]-2-one;1′-s-Butylspiro[indolin-3,3′-piperidin]-2-one;(S)-(+)-1′-Propylspiro[indolin-3,3′-piperidin]-2-one;1′-Propylspiro[4-azaindolin-3,3′-piperidin]-2-one;1′-Butylspiro[4-azaindolin-3,3′-piperidin]-2-one;1′-sec-Butylspiro[4-aza-indolin-3,3′-piperidin]-2-one;1′-Propyl-5-chlorospiro[7-aza-indolin-3,3′-piperidin]-2-one;1′-Propylspiro[7-azaindolin-3,3′-piperidin]-2-one;1′-Propyl-6-methylspiro[7-azaindolin-3,3′-piperidin]-2-one;1′-Propylspiro[isoindolin-3,3′-piperidin]-1-one hydrochloride;1′-Isopropylspiro[indoline-3,3′-piperidine]hydrochloride;2,3-Dihydro-1H-1′-Propylspiro[thieno[3,2-b]pyrrol-3,3′-piperidin]-2-one;2,3,1′,2′,3′,6′-Hexahydro-1H-spiro[thieno[3,2-b]pyrrol-3,3′-pyridin]-2-one;2,3,1′,2′,3′,6′-Hexahydro-1H-spiro[5,8-diazaindol-3,3′-pyridin]-2-one;1′,2′,3′,4′-Tetrahydrospiro[indolin-3,3′-(7H)-azepin]-2-one;1′,2′,3′,4′-Tetrahydrospiro[7-azaindolin-3,3′-(7H)-azepin)-2-one;1′-Ethyl-1′,2′,3′,4′-tetrahydrospiro[4-azaindolin-3,3′-(7H)-azepin)-2-one;6. A compound or a pharmaceutically acceptable salt thereof, accordingto claims 1-4 being(S)-5-Chloro-7-fluorospiro[indolin-3,3′-(1,2,3,6-tetrahydropyridin)]-2-one(S)-5-Methylspiro[7-azaindoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-one(S)-5,6-Dimethylspiro[7-azaindoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-one(S)-6-Methylspiro[7-azaindoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-one(S)-5-Chlorospiro[7-azaindoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-one(S)-5,7-Difluorospiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-one(S)-7-Chlorospiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-one(S)-7-Fluoro-5-methylspiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-one(S)-5-Methoxyspiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-one(S)-5-Chlorospiro[indoline-3,3′-piperidin]-2-one.
 7. A compound of theformula(S)-5-Chloro-7-fluorospiro[indolin-3,3′-(1,2,3,6-tetrahydropyridin)]-2-oneor a therapeutically acceptable salt thereof.
 8. A compound of theformula(S)-5-Methylspiro[7-azaindoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-oneor a therapeutically acceptable salt thereof.
 9. A compound of theformula(S)-5,6-Dimethylspiro[7-azaindoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-onor a therapeutically acceptable salt thereof.
 10. A compound of theformula(S)-6-Methylspiro[7-azaindoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-oneor a therapeutically acceptable salt thereof.
 11. A compound of theformula(S)-5-Chlorospiro[7-azaindoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-oneor a therapeutically acceptable salt thereof.
 12. A compound of theformula(S)-5,7-Difluorospiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-oneor a therapeutically acceptable salt thereof.
 13. A compound of theformula(S)-7-Chlorospiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-one or atherapeutically acceptable salt thereof.
 14. A compound of the formula(S)-7-Fluoro-5-methylspiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-oneor a therapeutically acceptable salt thereof.
 15. A compound of theformula(S)-5-Methoxyspiro[indoline-3,3′-(1,2,3,6-tetrahydropyridin)]-2-one or atherapeutically acceptable salt thereof.
 16. A compound of the formula(S)-5-Chlorospiro[indoline-3,3′-piperidin]-2-one or a therapeuticallyacceptable salt thereof.
 17. A process for the preparation of a compoundaccording to any one of claims 1 to 16 comprising the step of A)cyclizing a compound of the Formula VII

wherein L is a halogen or a trifluoromethylsulfonyl group, to give acompound of the general Formula I using palladium as a catalyst understandard conditions; or B) cyclizing a compound of the Formula XII

wherein X is and X is —NHCO—, —CONH—, —NH—SO₂—, or —SO₂NH—, A is oxygenor nitrogen, and PG is a suitable protecting group, such as Boc orbenzyl when A is nitrogen and 4-methoxybenzyl when A is oxygen, to givea compound of the general Formula I using formaldehyde under standardMannich conditions; or C) cyclizing a compound of the Formula VI

to give a compound of the general Formula I using formaldehyde understandard Mannich conditions; or D) cyclizing a compound of the Formula V

wherein PG is an amino protecting group, using a ruthenium or molybdenecomplex as a catalyst under standard reaction conditions to givecompounds of the general formula I, wherein Z is CH═CHCH₂—, or—CH2CH═CHCH₂—.
 18. A pharmaceutical formulation containing a compoundaccording to any one of claims 1 to 16 as active ingredient incombination with a pharmaceutically acceptable diluent or carrier. 19.Use of a compound according to any one of claims 1 to 16 in therapy. 20.Use of a compound according to any one of claims 1 to 16 for themanufacture of a medicament for the treatment of pain.
 21. Use of acompound according to any of claims 1 to 16 for the manufacture of amedicament for the treatment of neuropathic or central pain.
 22. Use ofa compound according to any of claims 20 and 21 for the manufacture of amedicament for oral use.
 23. A method for treatment or prophylaxis ofpain or discomfort, comprising administering to a mammal, including man,in need of such treatment an effective amount of a compound according toany one of claims 1 to
 16. 24. A method for treatment or prophylaxis ofneuropathic or central pain, comprising administering to a mammal,including man, in need of such treatment an effective amount of acompound according to any of claims 1-16.
 25. A method according to anyof claims 23 and 24 by oral administration.
 26. A pharmaceuticalformulation for use in the treatment or prophylaxis of pain ordiscomfort, comprising a compound of the formula I according to any oneof claims 1 to 16, in combination with a pharmaceutically acceptablecarrier or diluent.
 27. A pharmaceutical formulation for use in thetreatment or prophylaxis of neuropathic or central pain, comprising acompound according to any of claims 1-16, in combination with apharmaceutically acceptable carrier or diluent.
 28. A pharmaceuticalformulation according to any of claims 18, 26 and 27 for oraladministration